WO2009023179A2 - Entités chimiques bicycliques azotées pour traiter les infections virales - Google Patents

Entités chimiques bicycliques azotées pour traiter les infections virales Download PDF

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Publication number
WO2009023179A2
WO2009023179A2 PCT/US2008/009606 US2008009606W WO2009023179A2 WO 2009023179 A2 WO2009023179 A2 WO 2009023179A2 US 2008009606 W US2008009606 W US 2008009606W WO 2009023179 A2 WO2009023179 A2 WO 2009023179A2
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WIPO (PCT)
Prior art keywords
optionally substituted
chemical entity
alkyl
heterocycloalkyl
trifluoromethyl
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PCT/US2008/009606
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English (en)
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WO2009023179A3 (fr
Inventor
Franz Ulrich Schmitz
Vincent W-F Tai
Roopa Rai
Christopher Don Roberts
Ali Dehghani Mohammad Abadi
Subramanian Baskaran
Irina Slobodov
Jack Maung
Martin Leon Neitzel
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Genelabs Technologies, Inc.
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Priority to EP08795214A priority Critical patent/EP2187883A2/fr
Priority to CN200880111116A priority patent/CN101842098A/zh
Priority to US12/672,942 priority patent/US20120121540A1/en
Priority to MX2010001650A priority patent/MX2010001650A/es
Priority to CA2695989A priority patent/CA2695989A1/fr
Priority to BRPI0814939-9A2A priority patent/BRPI0814939A2/pt
Application filed by Genelabs Technologies, Inc. filed Critical Genelabs Technologies, Inc.
Priority to JP2010519999A priority patent/JP2010535773A/ja
Priority to EA201000201A priority patent/EA201000201A1/ru
Priority to AU2008287421A priority patent/AU2008287421A1/en
Publication of WO2009023179A2 publication Critical patent/WO2009023179A2/fr
Publication of WO2009023179A3 publication Critical patent/WO2009023179A3/fr
Priority to ZA2010/01523A priority patent/ZA201001523B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the Flaviviridae family of viruses is composed of three genera: pestivirus, flavivirus and hepacivirus (hepatitis C virus). Of these genera, flaviviruses and hepaciviruses represent important pathogens of man and are prevalent throughout the world. There are 38 flaviviruses associated with human disease, including the dengue fever viruses, yellow fever virus, and Japanese encephalitis virus. Flaviviruses cause a range of acute febrile illnesses and encephalitic and hemorrhagic diseases. Hepaciviruses currently infect approximately 2 to 3% of the world population and cause persistent infections leading to chronic liver disease, cirrhosis, hepatocellular carcinoma and liver failure.
  • Pestivirus infections in man have been implicated in several diseases including, but not limited to, congenital brain injury, infantile gastroenteritis and chronic diarrhea in human immunodeficiency virus (HIV).
  • HAV human immunodeficiency virus
  • HCV is a major causative agent for post-transfusion and for sporadic hepatitis. Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years.
  • interferon IFN-alpha
  • ribavirin the only acceptable treatment for chronic HCV is interferon (IFN-alpha) and/or ribavirin and this requires at least six (6) months of treatment, which can reduce the viral load and also improve liver function in some people.
  • IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory and anti-tumoral activities. IFN-alpha is an important regulator of immunological control. Treatment of HCV with interferon, however, has limited long term efficacy with a response rate about 25%. In addition, treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction.
  • Ribavirin (1-P-D-ribofuranosyl- 1 H- l,2,-4-triazole-3-carboxamide), an inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), enhances the efficacy of IFN-alpha in the treatment of HCV.
  • IFN interferon-alpha
  • Ribavirin causes significant hemolysis in 10-20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic.
  • standard therapy of chronic hepatitis C has been changed to the combination of PEG-IFN (pegylated interferon) plus ribavirin which leads only to small improvement.
  • W 3 is selected from CR 3 and NR 3 ;
  • W 4 is selected from CR 4 and N;
  • W 6 is selected from CR 6 and N;
  • W is selected from C and N;
  • W 9 is selected from C and N;
  • R is absent or is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 1 1 ⁇ NR 11 C(O)NR 10 R 11 , -NR 1 1 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)OR 13 , -CN, -NO 2 , and -C(O
  • R is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 ,
  • R 3 is absent or is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 1 1 , -NR 10 R 11 , -NR 11 C(O)NR 10 R", -NR 11 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)OR 13 , -CN, -NO 2 , and -C(O
  • R 4 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)OR 13 , -CN, -NO 2 , and -C(O)R
  • R 5 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 1 1 C(O)NR 10 R 11 , -NR 1 1 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 1 1 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R 1 1 , -C(O)OR 13 , -CN, -NO 2 , and -C(O
  • R 6 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R 1 1 , -C(O)OR 13 , -CN, -NO 2 , and -C(O)
  • R 7 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 1 1 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12
  • R 10 and R 11 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 10 and R 11 , taken together with any intervening atoms, form a ring system selected from optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • R 12 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 13 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R 16 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; provided that if W 1 is NR 1 and W 3 is NR 3 , then R 3 is absent; if W 3 is NR 3 and W 1 is NR 1 , then R 1 is absent; at least one of W 1 , W 3 , W 8 , and W 9 is N; no more than four of W 1 , W 3 , W 4 , W 6 , W 8 , and W 9 are N; and if W 1 is N, W 4 is N, and W 6 is CR 6 , then W 8 is not N; and further provided that the compound of Formula 1 is not
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of at least one chemical entity described herein.
  • composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of at least one chemical entity chosen from compounds of Formula 1 a
  • W 3 is selected from CR 3 and NR 3 ;
  • R 2 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 1 1 C(S)NR 10 R", -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR")NR 10 R", -C(O)NR 10 R", -C(O)OR 13 ,
  • R 3 is absent or is selected from halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR")NR 10 R", -C(O)NR 10 R 11 , -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12 ;
  • R 5 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 1 1 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R", -NR 1 1 S(O) 2 R 14 -NR 1 1 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR U )NR 10 R" , -C(O)NR 10 R", -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12 ;
  • R 6 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R", -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R", -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12 ;
  • R 7 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R", -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 1 1 , -C(O)NR 10 R", -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12 ;
  • R 10 and R 11 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 10 and R 11 , taken together with any intervening atoms, form a ring system selected from optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • R 12 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 1 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 16 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of at least one chemical entity chosen from
  • kits for treating a viral infection mediated at least in part by a virus in the flaviviridae family of viruses, such as HCV, in mammals which methods comprise administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a pharmaceutical composition described herein.
  • HCV hepacivirus
  • HIV human immunodeficiency virus
  • IFN interferon
  • IMPDH inosine 5 '-monophosphate dehydrogenase mg: milligram kg: kilogram
  • DPI dry powder inhaler nM: nano-Molar wt%: weight percent ⁇ M: micro-Molar
  • K Kelvin raL: milli-Liter
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • C x-y alkyl refers to alkyl groups having from x to y carbon atoms.
  • This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), ⁇ -propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), /i-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), r-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), ⁇ -propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-
  • Substituted alkyl refers to an alkyl group having from 1 to 5 and, in some embodiments, 1 to 3 or 1 or 2 substituents selected from alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,
  • Alkylidene or alkylene refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C u-V )alkylene refers to alkylene groups having from u to v carbon atoms.
  • the alkylidene and alkylene groups include branched and straight chain hydrocarbyl groups.
  • (Ci- 6 )alkylene is meant to include methylene, ethylene, propylene, 2-methypropylene, pentylene, and the like.
  • Substituted alkylidene or “substituted alkylene” refers to an alkylidene group having from 1 to 5 and, in some embodiments, 1 to 3 or 1 or 2 substituents selected from alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyl, cycloal
  • (C x -C y )alkenyl refers to alkenyl groups having from x to y carbon atoms and is meant to include for example, ethenyl, propenyl, 1,3-butadienyl, and the like.
  • Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents and, in some embodiments, 1 or 2 substituents selected from alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cyano, cycl
  • Alkynyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond.
  • alkynyl is also meant to include those hydrocarbyl groups having one triple bond and one double bond.
  • (C 2 -C 6 )alkynyl is meant to include ethynyl, propynyl, and the like.
  • Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents and, in some embodiments, from 1 or 2 substituents selected from alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, «-butoxy, t-butoxy, seobutoxy, and r ⁇ -pentoxy.
  • Substituted alkoxy refers to the group -O-(substituted alkyl) wherein substituted alkyl is as defined herein.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, substituted aryl-C(O)-, substituted hydrazino-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl
  • Acylamino refers to the groups -NR 20 C(O)alkyl, -NR 20 C(O)substituted alkyl, -NR 20 C(O)cycloalkyl, -NR 20 C(O)substituted cycloalkyl, -NR 20 C(O)alkenyl, -NR 20 C(O)substituted alkenyl, -NR 20 C(O)alkynyl, -NR 20 C(O)substit ⁇ ted alkynyl, -NR 20 C(O)aryl, -NR 20 C(O)substituted aryl, -NR 20 C(O)heteroaryl, -NR 20 C(O)substituted heteroaryl, -NR 20 C(O)heterocyclic, and -NR 20 C(O)substituted heterocyclic wherein R 20 is hydrogen or alkyl and wherein alkyl, substituted alkyl, substituted al
  • Acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(0)O, substituted alkenyl-C(0)O, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(0)0-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
  • Substituted amino refers to the group -NR 21 R 22 where R 21 and R 22 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cylcoalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -S ⁇ 2 -heteroaryl, -SO 2 -substituted heteroaryl, -
  • R ' is hydrogen and R 22 is alkyl
  • the substituted amino group is sometimes referred to herein as alkylamino.
  • R 21 and R 22 are alkyl
  • the substituted amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R 21 or R 22 is hydrogen but not both.
  • a disubstituted amino it is meant that neither R 21 nor R 22 are hydrogen.
  • “Hydroxyamino” refers to the group -NHOH.
  • Alkoxyamino refers to the group -NHO-alkyl wherein alkyl is defined herein.
  • Aminocarbonyl refers to the group -C(O)NR 23 R 24 where R 23 and R 24 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, and acylamino, and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
  • Aminothiocarbonyl refers to the group -C(S)NR 23 R 24 where R 23 and R 24 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Aminocarbonylamino refers to the group -NR 20 C(O)NR 23 R 24 where R 20 is hydrogen or alkyl and R 23 and R 24 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined
  • Aminothiocarbonylamino refers to the group -NR 20 C(S)NR 23 R 24 where R 20 is hydrogen or alkyl and R 23 and R 24 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are
  • Aminocarbonyloxy refers to the group -0-C(O)NR 23 R 24 where R 23 and R 24 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Aminosulfonyl refers to the group -SO 2 NR 23 R 24 where R 23 and R 24 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Aminosulfonyloxy refers to the group -0-SO 2 NR 23 R 24 where R 23 and R 24 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Aminosulfonylamino refers to the group -NR 20 -SO 2 NR 23 R 24 where R 20 is hydrogen or alkyl and R 23 and R 24 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 23 and R 24 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocycl
  • Aryl or “Ar” refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
  • Aryl or “Ar” applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).
  • Substituted aryl refers to aryl groups which are substituted with 1 to 8 and, in some embodiments, 1 to 5, 1 to 3, or 1 or 2 substituents selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy,
  • Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthyloxy.
  • Substituted aryloxy refers to the group -O-(substituted aryl) where substituted aryl is as defined herein.
  • Arylthio refers to the group -S-aryl, where aryl is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
  • Hydrazino refers to the group -NHNH 2 .
  • Substituted hydrazino refers to the group -NR 26 NR 27 R 28 where R 26 , R 27 , and R 28 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO 2 -alkyl,
  • R 27 and R 28 are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R 27 and R 28 are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Carboxyl or “carboxy” refers to -COOH or salts thereof.
  • Carboxyl ester or “carboxy ester” refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkyl, alky
  • (Carboxyl ester)amino refers to the group -NR 20 -C(O)O-alkyl, -NR 20 -C(O)O-substituted alkyl, -NR 20 -C(O)O-alkenyl, -NR 20 -C(O)O-substituted alkenyl, -NR 20 -C(O)O-alkynyl, -NR 20 -C(O)O-substituted alkynyl, -NR 20 -C(O)O-aryl, -NR 20 -C(O)O-substituted aryl, -NR 20 -C(O)O-cycloalkyl, -NR 20 -C(O)O-substituted cycloalkyl, -NR 20 -C(O)O-heteroaryl, -NR 20 -C(O)O-substituted heteroaryl
  • (Carboxyl este ⁇ xy) refers to the group -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic, and -O-C(O)
  • Cycloalkyl refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7, 8,-tetrahydronaphthalene-5-yl).
  • Cycloalkyl includes cycloalkenyl groups.
  • cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl.
  • C u-V cycloalkyl refers to cycloalkyl groups having u to v carbon atoms.
  • Cycloalkylene refer to divalent cycloalkyl groups as defined herein.
  • Examples of cycloalkyl groups include those having three to six carbon ring atoms such as cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.
  • Substituted cycloalkyl refers to a cycloalkyl group, as defined herein, having from
  • substituents selected from oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino,
  • Cycloalkyloxy refers to -O-cycloalkyl wherein cycloalkyl is as defined herein.
  • Substituted cycloalkyloxy refers to -O-(substituted cycloalkyl) wherein substituted cycloalkyl is as defined herein.
  • Cycloalkylthio refers to -S-cycloalkyl wherein cycloalkyl is as defined herein.
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyl).
  • Halo or "halogen” refers to fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to substitution of alky 1 groups with 1 to 5 or in some embodiments
  • Haloalkoxy refers to substitution of alkoxy groups with 1 to 5 or in some embodiments 1 to 3 halo groups.
  • Heteroaryl refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl).
  • single ring e.g. imidazolyl
  • multiple ring systems e.g. benzimidazol-2-yl and benzimidazol-6-yl.
  • the term “heteroaryl” applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, quinazolinonyl, benzimidazolyl, benzisoxazolyl, or benzo thienyl.
  • Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to
  • Heteroaryloxy refers to -O-heteroaryl wherein heteroaryl is as defined herein.
  • Substituted heteroaryloxy refers to the group -O-(substituted heteroaryl) wherein substituted heteroaryl is as defined herein.
  • Heteroarylthio refers to the group -S-heteroaryl wherein heteroaryl is as defined herein.
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl) wherein substituted heteroaryl is as defined herein.
  • Aromatic ring systems may be depicted as a circle, which represents the (4n+2) ⁇ electrons, enclosed by an outer cyclic structure, such as, a hexagon or pentagon.
  • an outer cyclic structure such as, a hexagon or pentagon.
  • each of the rings in the compound of Formula 1 is aromatic.
  • Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems.
  • heterocyclic For multiple ring systems having aromatic and/or non-aromatic rings, the terms “heterocyclic”, “heterocycle”,
  • heterocycloalkyl or “heterocyclyl” apply when there is at least one ring heteroatom and the point of attachment is at an atom of a non-aromatic ring (e.g. l,2,3,4-tetrahydroquinoline-3-yl,
  • the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties.
  • the heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl, piperazinyl, N-methylpyrrolidin-3-yl, 3-pyrrolidinyl, 2-pyrrolidon-l-yl, morpholinyl, and pyrrolidinyl.
  • a prefix indicating the number of carbon atoms (e.g., C 3 -Ci 0 ) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
  • Substituted heterocyclic or “Substituted heterocycle” or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclic groups, as defined herein, that are substituted with from 1 to 5 or in some embodiments 1 to 3 of the substituents as defined for substituted cycloalkyl.
  • Heterocyclyloxy refers to the group -O-heterocycyl wherein heterocyclyl is as defined herein.
  • Substituted heterocyclyloxy refers to the group -O-(substituted heterocycyl) wherein substituted heterocyclyl is as defined herein.
  • Heterocyclylthio refers to the group -S-heterocycyl wherein heterocyclyl is as defined herein.
  • Substituted heterocyclylthio refers to the group -S-(substituted heterocycyl) wherein substituted heterocyclyl is as defined herein.
  • heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydro
  • Niro refers to the group -NO 2 .
  • Oxide refers to products resulting from the oxidation of one or more heteroatoms.
  • Examples include N-oxides, sulfoxides, and sulfones.
  • Spirocycloalkyl refers to a 3 to 10 member cyclic substituent formed by replacement of two hydrogen atoms at a common carbon atom with an alkylene group having 2 to 9 carbon atoms, as exemplified by the following structure wherein the methylene group shown here attached to bonds marked with wavy lines is substituted with a spirocycloalkyl group:
  • Sulfonyl refers to the divalent group -S(O) 2 -.
  • Substituted sulfonyl refers to the group -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -alkynyl, -SO 2 -substituted alkynyl, -SO 2 -cycloalkyl, -SO 2 -substituted cylcoalkyl, -S ⁇ 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic, -SO 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Thioacyl refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, wherein alkyl,
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
  • Thiocyanate refers to the group -SCN.
  • Compound and “compounds” as used herein refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae, including the racemates, stereoisomers, and tautomers of the compound or compounds.
  • Solvate or “solvates” of a compound refer to those compounds, where compounds is as defined above, that are bound to a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvates of a compound includes solvates of all forms of the compound.
  • solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
  • Suitable solvates include water.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.),
  • Patient refers to mammals and includes humans and non-human mammals.
  • Treating" or “treatment” of a disease in a patient refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease;
  • arylalkyloxycabonyl refers to the group (aryl)-(alkyl)-O-C(O)-.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
  • impermissible substitution patterns are well known to the skilled artisan.
  • W 1 is selected from CR 1 and NR 1 ;
  • W 3 is selected from CR 3 and NR 3 ;
  • W 4 is selected from CR 4 and N;
  • W 6 is selected from CR 6 and N;
  • W is selected from C and N;
  • W 9 is selected from C and N;
  • R 1 is absent or is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R", -NR 1 1 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)OR 13 , -CN, -NO 2 , and -C(O
  • R 2 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 ,
  • R 3 is absent or is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 1 1 C(O)NR 10 R 11 , -NR 1 1 C(S)NR 10 R", -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R", -C(O)NR 10 R", -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12
  • R is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 11 JNR 10 R 11 , -C(O)NR 10 R", -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12 ;
  • R 5 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 1 1 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R", -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 11 JNR 10 R 11 , -C(O)NR 10 R", -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12 ;
  • R 6 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R", -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 11 JNR 10 R 11 , -C(O)NR 10 R 1 1 , -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12
  • R 7 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R", -NR 1 1 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 11 JNR 10 R 11 , -C(O)NR 10 R", -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12 ;
  • R 10 and R 11 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 10 and R 1 ', taken together with any intervening atoms, form a ring system selected from optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • R 12 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 13 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 16 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; provided that if W 1 is NR 1 and W 3 is NR 3 , then R 3 is absent; if W 3 is NR 3 and W 1 is NR 1 , then R 1 is absent; at least one of W 1 , W 3 , W 8 , and W 9 is N; no more than four of W 1 , W 3 , W 4 , W 6 , W 8 , and W 9 are N; and if W 1 is N, W 4 is N, and W 6 is CR 6 , then W 8 is not N; and further provided that the compound of Formula 1 is not
  • the compound of Formula 1 is selected from the following compounds:
  • the compound of Formula 1 is selected from the following compounds:
  • the compound of Formula 1 is selected from the following compounds:
  • the compound of Formula 1 is selected from the following compounds:
  • the compound of Formula 1 is selected from the following compounds:
  • the compound of Formula 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe-N-(2-aminoe-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 2 is selected from optionally substituted alkyl, -NR 11 S(O) 2 R 14 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(O)OR 13 -C(O)NR 10 R 11 , and -C(O)OR 13 .
  • R 2 is lower alkyl substituted with -NR 10 R 1 ⁇ where R 10 and
  • R 1 ' are as described herein.
  • R 2 is -CH 2 -NR 10 R 1 ', where R 10 and R 1 ' are as described herein.
  • R 2 is lower alkyl substituted with -NR 10 R 1 ' and R 10 and R 1 1 , together with any intervening atoms, form an optionally substituted heterocycloalkyl, as described herein.
  • R 2 is -CH 2 -NR 10 R 11 and R 10 and R 11 , together with any intervening atoms, form an optionally substituted heterocycloalkyl, as described herein.
  • R 2 is lower alkyl substituted with -C(O)NR 10 R 1 ', where R 10 and R 11 are as described herein. In some embodiments, R 2 is -CH 2 -C(O)NR 10 R 11 , where R 10 and
  • R 11 are as described herein.
  • R 2 is -C(O)NR 10 R 11 .
  • R 1 is selected from lower alkyl and hydrogen.
  • R 10 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl. In some embodiments,
  • R 10 is -(CR 17 R 18 ) n R 19 , wherein R 17 and R 18 are independently selected from hydrogen, carboxy, optionally substituted aminocarbonyl, lower carboxy ester, and lower alkyl; n is 0, 1 or 2; and
  • R 19 is chosen from optionally substituted aryl and optionally substituted heteroaryl.
  • R 10 is benzyl, thiophen-2-yl-ethyl, thiophen-3-yl-methyl, furan-2-yl-methyl, and furan-3-yl-methyl, each of which is optionally substituted.
  • R 11 is selected from lower alkyl and hydrogen.
  • R 10 and R 1 ' together with any intervening atoms, form an optionally substituted heterocycloalkyl.
  • R 10 and R 11 together with any intervening atoms, form a substituted 3- to 7-membered nitrogen containing heterocycloalkyl which optionally further includes one or two additional heteroatoms chosen from N, O, S, S(O),
  • Y is a bond or is selected from -NR 10 -, -NR 11 SO 2 -, -O-, -S-, -C(O)NR 10 -, and -S(O) 2 R 10 -;
  • R 30 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 31 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, -OH, -SH, -NO 2 , -NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)OR 13 , -SO 2 NR 10 R", -NR 1 1 C(S)NR 10 R 11 , -NR 11 C(O)NR 10 R 1 1 , -CN, -NR 11 SO 2 R 14 , and -NR 11 CO 2 R 13 .
  • R 1 and R 11 together with any intervening atoms, form a substituted 3- to 7-membered nitrogen containing heterocycloalkyl which optionally further includes one or two additional heteroatoms chosen from N, O, S, S(O), S(O) 2 , and P(O), wherein said 3- to 7-membered nitrogen containing heterocycloalkyl is substituted with a group -Y-R 30 and optionally substituted with a second group R 31 , wherein
  • Y is a bond or is selected from -0-, -S-, -C(O)NR 10 -, and -S(O) 2 R 10 -;
  • R 30 is selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 31 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, -NO 2 , -NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)OR 13 , -SO 2 NR 10 R 11 , -NR 11 C(S)NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -CN, -NR 11 SO 2 R 14 , and -NR 11 CO 2 R 13 .
  • Y is a bond or is selected from -NR 10 - and -0-. In some embodiments, Y is a bond or is -0-. In some embodiments, Y is a bond. [0129] In some embodiments, R 30 is selected from optionally substituted aryl and optionally substituted heteroaryl. In some embodiments, R 3 is selected from phenyl, thiophen-2-yl, thiophen-3-yl, furan-2-yl, furan-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyrazol-4-yl, imidazol-4-yl, and imidazol-2-yl.
  • R 30 is selected from phenyl, thiophen- 2-yl, thiophen-3-yl, furan-2-yl, and furan-3-yl. In some embodiments, R is phenyl. In some embodiments, R 30 is optionally substituted alkyl. In some embodiments, R 30 is optionally substituted lower alkyl. In some embodiments, R 30 is lower alkyl. In some embodiments, R 3 is methyl.
  • R 2 is -C(O)NR 10 R 1 ' and R 10 and R 1 ⁇ together with any intervening atoms, form a pyrrolidinyl, piperidinyl, piperazinyl, 5,6-dihydropyridin-l(2H)-yl, 4,5-dihydro-lH-pyrazol-l-yl, 2,5-dihydro-lH-pyrrol-l-yl, or azetidinyl ring, wherein said ring is substituted with a group -Y-R 30 and optionally substituted with a second group R 31 as described above.
  • R 2 is lower alkyl substituted with -C(O)NR 10 R 1 ' and R 10 and
  • R together with any intervening atoms, form a pyrrolidinyl, piperidinyl, piperazinyl, 5,6- dihydropyridin-l(2H)-yl, 4,5-dihydro-lH-pyrazol-l-yl, 2,5-dihydro-lH-pyrrol-l-yl, or azetidinyl ring, wherein said ring is substituted with a group -Y-R 30 and optionally substituted with a second group R as described above.
  • R is -CH 2 - substituted with
  • -C(O)NR 10 R 11 and R 10 and R 11 together with any intervening atoms, form a pyrrolidinyl, piperidinyl, piperazinyl, 5,6-dihydropyridin-l(2H)-yl, 4,5-dihydro-lH-pyrazol-l-yl, 2,5-dihydro- lH-pyrrol-1-yl, or azetidinyl ring, wherein said ring is substituted with a group -Y-R 30 and optionally substituted with a second group R 31 as described above.
  • R 2 is optionally substituted heteroaryl. In some embodiments,
  • R is isoxazol-5-yl or [l,2,4]oxadiazol-5-yl, each of which is optionally substituted.
  • R 2 is isoxazol-5-yl or [l,2,4]oxadiazol-5-yl, each of which is optionally substituted with a group chosen from optionally substituted aryl and optionally substituted alkyl.
  • R 2 is isoxazol-5-yl or [l,2,4]oxadiazol-5-yl, each of which is optionally substituted with a group chosen from optionally substituted phenyl, optionally substituted benzyl, and optionally substituted phenoxymethyl. In some embodiments, R 2 is isoxazol-5-yl or
  • R 3 is selected from optionally substituted alkyl and halogen.
  • R 3 is selected from lower alkyl and halogen. In some embodiments, R 3 is halogen. In some embodiments, R 3 is selected from chlorine and bromine. In some embodiments, R 3 is chlorine. In some embodiments, R 3 is hydrogen.
  • R 4 is selected from hydrogen, optionally substituted alkyl,
  • R 1 1 is hydrogen.
  • R 10 is selected from optionally substituted alkyl and optionally substituted cycloalkyl.
  • R 4 is selected from hydrogen and optionally substituted lower alkyl. In some embodiments, R 4 is hydrogen.
  • R 4 is -CN.
  • R 5 is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl. In some embodiments, R 5 is selected from optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments, R 5 is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • R 5 is selected from pyrid-3-yl, pyrazol-4-yl, phenyl, furan-2-yl, furan-3-yl, thiophen-2-yl, and thiophen-3-yl, each of which is optionally substituted. In some embodiments, R 5 is selected from phenyl, furan-2-yl, furan-3-yl, thiophen-2-yl, and thiophen-3-yl, each of which is optionally substituted.
  • R 5 is selected from phenyl, furan-2-yl, furan-3-yl, thiophen-2-yl, and thiophen-3-yl, each of which is optionally substituted with one or two groups chosen from lower alkyl, halogen, morpholinyl, trifluoromethyl, and lower alkoxy. In some embodiments, R 5 is selected from phenyl, 3 -fluorophenyl, furan-2-yl, furan-3-yl, thiophen-2-yl, and thiophen-3-yl.
  • R 6 is selected from hydrogen, halogen, optionally substituted alkyl, -OR 15 , -S(O)NR 10 R 11 , -C(O)R 12 , -NO 2 , -C(O)NR 10 R 11 , and -NR 10 R 11 .
  • R 6 is selected from hydrogen, halogen, optionally substituted alkyl, -S(O)NR 10 R 11 , -C(O)R 12 , -NO 2 , -C(O)NR 10 R 11 , and -NR 10 R 11 .
  • R 11 is hydrogen.
  • R 10 is selected from optionally substituted alkyl and optionally substituted cycloalkyl. In some embodiments, R 10 and R 11 , taken together with any intervening atoms, form an optionally substituted heterocycloalkyl ring.
  • R 6 is selected from hydrogen, halogen, and optionally substituted alkyl. In some embodiments, R 6 is selected from hydrogen and halogen. In some embodiments, R 6 is hydrogen.
  • R 7 is selected from halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, heterocycloalkyl, optionally substituted aryl, -SO 2 NR 10 R 11 , and -NR 10 R 11 .
  • R 7 is selected from halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, heterocycloalkyl, optionally substituted aryl, and -NR 10 R 11 .
  • R 7 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, and -NR 10 R 1 1 .
  • R 7 is selected from optionally substituted alkyl, optionally substituted alkoxy, and -NR 10 R 11 .
  • R 7 is selected from optionally substituted lower alkoxy and optionally substituted lower alkyl.
  • R 7 is polyhalogenated lower alkoxy. In some embodiments,
  • R 7 selected from trifluoromethoxy and difluorochloromethoxy.
  • R 7 is polyhalogenated lower alkyl. In some embodiments, R 7 is polyhalogenated methyl. In some embodiments, R 7 is selected from trifluoromethyl and difluorochloromethyl. In some embodiments, R 7 is trifluoromethyl.
  • R 7 is -NR 10 R 11 .
  • R 11 is hydrogen.
  • R 10 is optionally substituted lower alkyl.
  • R 10 is methyl.
  • R 10 is 2-hydroxyethyl.
  • the compound of Formula 1 is chosen from the compounds set forth in Table 1, Table 2, and Table 3.
  • 2-carboxylic acid 304 3 (2-Cyclopropyl-vinyl)-6-(3 -fluoro- phenyl)-8-trifluoromethyl-iniidazo[l,2- a]pyridine-2-carboxylic acid (thiophen- 2-ylmethyl)-amide
  • composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of at least one chemical entity described herein.
  • composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of at least one chemical entity chosen from compounds of Formula 1 a
  • W 3 is selected from CR 3 and NR 3 ;
  • R 2 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R 1 1 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12
  • R 3 is absent or is selected from halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 1 1 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12 ;
  • R 5 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 1 1 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 1 1 , -C(O)NR 10 R 1 1 , -C(O)OR 13 , -CN, -NO 2 , and -C(O)
  • R 6 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R 1 1 , -C(O)OR 13 , -CN, -NO 2 , and -C(O)
  • R 7 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 15 , -SR 15 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 NR 10 R 11 , -NR 10 R 11 , -NR 11 C(O)NR 10 R 1 1 , -NR 11 C(S)NR 10 R 11 , -NR 11 S(O) 2 R 14 -NR 11 C(O)OR 13 , -NR 11 C(O)R 12 , -C(NR 1 ⁇ NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)OR 13 , -CN, -NO 2 , and -C(O)R 12
  • R 10 and R 11 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 10 and R 11 , taken together with any intervening atoms, form a ring system selected from optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • R 12 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 13 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R 16 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 2 is selected from optionally substituted alkyl, -NR 11 S(O) 2 R 14 , -NR 11 C(O)NR 10 R 11 , -NR 11 C(O)OR 13 -C(O)NR 10 R 11 , and -C(O)OR 13 .
  • R 2 is -C(O)NR 10 R 11 .
  • R 10 is selected from lower alkyl and hydrogen.
  • R 10 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl.
  • R 10 is -(CR 17 R 18 ) n R 19 , wherein R 17 and R 18 are independently selected from hydrogen, carboxy, optionally substituted aminocarbonyl, lower carboxy ester, and lower alkyl; n is O, 1 or 2; and R 19 is chosen from optionally substituted aryl and optionally substituted heteroaryl.
  • R 10 is benzyl, thiophen-2-yl-ethyl, thiophen-3-yl-methyl, furan-2-yl- methyl, and furan-3-yl-methyl, each of which is optionally substituted.
  • R 10 and R 1 ⁇ together with any intervening atoms form an optionally substituted heterocycloalkyl.
  • R 10 and R 11 together with any intervening atoms, form a substituted 3- to 7-membered nitrogen containing heterocycloalkyl which optionally further includes one or two additional heteroatoms chosen from N, O, S and P(O), wherein said 3- to 7-membered nitrogen containing heterocycloalkyl is substituted with a group -Y-R 30 and optionally substituted with a second group R 31 , wherein
  • Y is a bond or is selected from -NR 10 -, -NR 11 SO 2 -, -0-, -S-, -C(O)NR 10 -, and -S(O) 2 R 10 -;
  • R 30 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 31 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, -OH, -SH, -NO 2 , -NR 10 R 1 1 , -C(O)NR 10 R 1 1 , -C(O)OR 13 , -SO 2 NR 10 R 11 , -NR 11 C(S)NR 10 R 11 , -NR 1 1 C(O)NR 10 R 1 1 , -CN, -NR 11 SO 2 R 14 , and -NR 1 1 CO 2 R 13 .
  • R 10 and R 1 1 together with any intervening atoms, form an optionally substituted heterocycloalkyl.
  • R 10 and R 11 together with any intervening atoms, form a substituted 3- to 7-membered nitrogen containing heterocycloalkyl which optionally further includes one or two additional heteroatoms chosen from N, O, S and P(O), wherein said 3- to 7-membered nitrogen containing heterocycloalkyl is substituted with a group -Y-R 30 and optionally substituted with a second group R 31 , wherein
  • Y is a bond or is selected from -0-, -S-, -C(O)NR 10 -, and -S(O) 2 R 10 -;
  • R 30 is selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 31 is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, -NO 2 , -NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)OR 13 , -SO 2 NR 10 R 11 , -NR 11 C(S)NR 10 R 11 , -NR 11 C(O)NR 10 R 11 , -CN, -NR 11 SO 2 R 14 , and -NR 11 CO 2 R 13 .
  • Y is a bond or is chosen from -NR 1 - and -0-. In some embodiments of compounds of Formula Ia, Y is a bond or is -0-. In some embodiments of compounds of Formula Ia, Y is a bond.
  • R 30 is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • R is selected from phenyl, thiophen-2-yl, thiophen-3-yl, furan-2-yl, furan-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyrazol-4-yl, imidazol-4-yl, and imidazol-2-yl.
  • R 30 is selected from phenyl, thiophen-2-yl, thiophen- 3-yl, furan-2-yl, and furan-3-yl of compounds of Formula Ia. In some embodiments, R 30 is phenyl. In some embodiments of compounds of Formula Ia, R 30 is optionally substituted alkyl. In some embodiments of compounds of Formula Ia, R 30 is optionally substituted lower alkyl. In some embodiments of compounds of Formula Ia, R 30 is lower alkyl. In some embodiments of compounds of Formula Ia, R 30 is methyl.
  • R 2 is optionally substituted heteroaryl.
  • R 2 is isoxazol-5-yl or [l,2,4]oxadiazol-5-yl, each of which is optionally substituted.
  • R 2 is isoxazol-5-yl or [l,2,4]oxadiazol-5-yl, each of which is optionally substituted with a group chosen from optionally substituted aryl and optionally substituted alkyl.
  • R 2 is isoxazol-5-yl or [l,2,4]oxadiazol-5-yl, each of which is optionally substituted with a group chosen from optionally substituted phenyl, optionally substituted benzyl, and optionally substituted phenoxy methyl.
  • R 2 is isoxazol-5-yl or [l,2,4]oxadiazol-5-yl, each of which is optionally substituted with a group chosen from phenyl, benzyl, and phenoxy methyl.
  • R 3 is halogen. In some embodiments of compounds of Formula Ia, R 3 is selected from chlorine and bromine. In some embodiments of compounds of Formula Ia, R 3 is chlorine.
  • R 5 is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl. In some embodiments of compounds of Formula Ia, R 5 is selected from optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments of compounds of Formula Ia, R 5 is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • R 5 is selected from pyrid-3-yl, pyrazol-4-yl, phenyl, furan-2-yl, furan-3-yl, thiophen-2-yl, and thiophen-3-yl, each of which is optionally substituted. In some embodiments of compounds of Formula Ia, R 5 is selected from phenyl, furan-2-yl, furan-3-yl, thiophen-2-yl, and thiophen-3-yl, each of which is optionally substituted.
  • R 5 is selected from phenyl, furan-2-yl, furan-3-yl, thiophen-2-yl, and thiophen-3-yl, each of which is optionally substituted with one or two groups chosen from lower alkyl, halogen, morpholinyl, trifluoromethyl, and lower alkoxy.
  • R 5 is selected from phenyl, 3 -fluorophenyl, furan-2-yl, furan-3-yl, thiophen-2-yl, and thiophen-3-yl.
  • R 6 is selected from hydrogen, halogen, optionally substituted alkyl, -OR 15 , -S(O)NR 10 R 11 , -C(O)R 12 , -NO 2 , -C(O)NR 10 R 11 , and -NR 10 R 11 .
  • R 6 is selected from hydrogen, halogen, optionally substituted alkyl, -S(O)NR 10 R 11 , -C(O)R 12 , -NO 2 , -C(O)NR 10 R 11 , and -NR 10 R 1 1 .
  • R 1 1 is hydrogen.
  • R 10 is selected from optionally substituted alkyl and optionally substituted cycloalkyl.
  • R 10 and R 1 ' taken together with any intervening atoms, form an optionally substituted heterocycloalkyl ring.
  • R 6 is selected from hydrogen, halogen, and optionally substituted alkyl. In some embodiments of compounds of Formula Ia,
  • R 6 is selected from hydrogen and halogen.
  • R 6 is hydrogen
  • R 7 is selected from halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, heterocycloalkyl, optionally substituted aryl, -SO 2 NR 10 R 11 , and -NR 10 R 11 .
  • R 7 is selected from halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, heterocycloalkyl, optionally substituted aryl, and -NR 10 R 11 .
  • R 7 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, and -NR 10 R 11 . In some embodiments of compounds of Formula Ia, R 7 is selected from optionally substituted alkyl, optionally substituted alkoxy, and -NR 10 R 1 1 . In some embodiments of compounds of Formula Ia, R 7 is selected from optionally substituted lower alkoxy and optionally substituted lower alkyl.
  • R 7 is polyhalogenated lower alkoxy. In some embodiments of compounds of Formula Ia, R 7 selected from trifluoromethoxy and difluorochloromethoxy.
  • R 7 is polyhalogenated lower alkyl. In some embodiments of compounds of Formula Ia, R is polyhalogenated methyl. In some embodiments of compounds of Formula Ia, R 7 is selected from trifluoromethyl and difluorochloromethyl. In some embodiments of compounds of Formula Ia, R 7 is trifluoromethyl.
  • R 7 is -NR 10 R 1 ' .
  • R 11 is hydrogen.
  • R 10 is optionally substituted lower alkyl.
  • R is methyl.
  • R 10 is 2-hydroxyethyl.
  • composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of at least one chemical entity chosen from
  • the methods of this specification employ protecting groups which are necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the provided chemical entities may contain one or more chiral centers and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures.
  • stereoisomers and enriched mixtures are included within the scope of this specification, unless otherwise indicated.
  • Pure stereoisomers may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce or Sigma (St. Louis, Missouri, USA).
  • reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10 °C to about 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
  • solvent each mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N- methylpyrrolidone (“NMP”), pyridine and the like].
  • solvents used in the reactions described herein are inert organic solvents.
  • one cc (or mL) of solvent constitutes a volume equivalent
  • Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.
  • the (R)- and (S)-isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other
  • Scheme 1 shows a method of assembling the imidazopyridine scaffold with various substituents.
  • 2-Amino pyridine substituted with R 7 is brominated by treatment with NBS in a solvent such as DMF.
  • Substituted 2-aminopyridine 1.2 is cyclized to the imidazopyridine 1.3 by heating it with ethyl bromopyruvate in a solvent like DMF.
  • Treatment of intermediate 1.3 with NCS in DMF affords the 3-chlorosubstituted imidazopyridine 1.4.
  • Palladium mediated coupling reactions such as Suzuki couplings, Sonogashira couplings and Heck couplings can afford diversity at R 5 in intermediates 1.5.
  • Hydrolysis of the ester is effected by refluxing in 4N HCl and acetonitrile as co-solvent.
  • the acid 1.6 is converted to amides 1.7 through standard amide coupling agents such as HBTU.
  • Scheme 2 shows a general scheme for the synthesis of purine analogs such as 2.5.
  • An appropriately substituted amino dichloropyrimidine (2.1) can be converted to diaminopyrimidine such as 2.2 by stirring with an appropriately substituted primary amine (R 3 NH 2 ).
  • Reaction with ethyl glyoxalate affords the ester intermediate 2.3.
  • Paladium mediated coupling reactions such as Suzuki couplings, Sonogashira couplings and Heck couplings can afford diversity.
  • Hydrolysis of the ester followed by amide coupling can afford the desired purine amide analogs such as 2.5.
  • Scheme 3 shows a general scheme for the synthesis of pyrrolopyrimidines such as 3.7.
  • the BOC protected amino bromo pyrimidine (3.2) can be prepared from the appropriately substituted amino bromo pyrimidine (3.1) using standard methods. Sonogashira coupling with ethyl propiolate would afford the alkyne 3.3.
  • Cyclization to the 2-substituted pyrrolopyrimidine 3.4 can be done by heating with tetrabutyl ammonium fluoride. Heating 3.4 with an alkyl halide results in N-alkylation to the intermediate 3.5.
  • Scheme 4 describes the synthesis of imidazopyridine analogs such as 4.5.
  • the appropriately substituted 3 -amino 2-chloropyridine 4.1 when heated with a primary amine such as R3NH 2 affords the 2,3-diaminopyridine 4.2.
  • Reaction with ethyl glyoxalate affords the ester intermediate 4.3.
  • Hydrolysis of the ester followed by amide coupling can afford the desired imidazopyridine amide analogs such as 4.5.
  • Scheme 5 describes the synthesis of pyrrolopyridine analogs such as 5.5.
  • the appropriately substituted 3-aminopyridine such as 5.1 can be brominated at the 2-position by reaction with NBS. Sonogashira coupling with ethyl propiolate would afford the alkyne 5.3.
  • Cyclization to the 2-substituted pyrolopyridine can be done by first protecting the amine as the Boc derivative, then heating with tetrabutyl ammonium fluoride. Hydrolysis of the ester is effected by refluxing in 4N HCl and acetonitrile as co-solvent. The resulting acid (5.4) is converted to amides 5.5 through standard amide coupling agents such as HBTU.
  • Scheme 6 shows the synthesis of pyrazolo[l ,5-a]pyridines.
  • Compounds can be prepared by 1,3-dipolar cycloaddition of substituted N-aminopyridines 6.2 with an alkyne such as methyl propiolate, dimethyl acetylenedicarboxylate or the like.
  • N-amination of pyridines can be carried out by treating substituted pyridines 6.1 with animating reagents such as hydroxylamine-O-sulfonic acid, O-mesitylenesulfonylhydroxylamine (MSH), O-(2,4- dinitrophenyl)hydroxylamine (Ref: C. Legault, A. B. Charette, J. Org.
  • Substituted pyridines can in turn be prepared by a variety of methods known in the literature such as the Chichibabin pyridine synthesis, Hantzsch pyridine synthesis, Guareschi-Thorpe pyridine synthesis, Bohlmann-Rahtz pyridine synthesis, Krohnke pyridine synthesis or Boger pyridine synthesis.
  • Chichibabin pyridine synthesis Hantzsch pyridine synthesis
  • Guareschi-Thorpe pyridine synthesis Guareschi-Thorpe pyridine synthesis
  • Bohlmann-Rahtz pyridine synthesis Bohlmann-Rahtz pyridine synthesis
  • Krohnke pyridine synthesis or Boger pyridine synthesis.
  • compounds of formula 6.3 can be prepared in which dimethyl acetylenedicarboxylate is treated with optionally substituted N-aminopyridine in the presence of a suitable base such as potassium carbonate, DBU and the like, in a suitable solvent such as DMF, and the like.
  • a suitable base such as potassium carbonate, DBU and the like
  • DMF a suitable solvent
  • compounds of formula 6.4 can be prepared by the acidic hydrolysis and chemoselective decarboxylation with a suitable acid such as concentrated sulfuric acid and the like under heating conditions.
  • compounds of formula 6.5, in which R 2 is C(O)NR 10 R 1 ' can be prepared by reacting a deprotected carboxylic acid with a primary or secondary amine or amine salt, e.g. amine of the formula NR 10 R 11 .
  • the reaction can be carried out with the acid in the presence of a coupling agent such as benzotriazole-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP®), bromo- tris-pyrrolidino-phosphonium hexafluorophosphate (PyB roP®), 2-(lH-benzotriazole-l-yl)- 1,1,3,3-tetramethylaminium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), or 1,3-dicyclohexylcarbodiimide (DCC) or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) optionally in the presence of 1 -hydroxybenzotri
  • a base such as N ,N- diisopropylethylamine, triethylamine, or N-methylmorpholine can be used.
  • the reaction is carried out in suitable organic solvents, such as DMF, THF and the like.
  • suitable amines and amine salts are either commercially available or they can be prepared from commercial available starting materials by methods known in the art.
  • a compound of formula 7.4 or 7.5 in which R 7 is Br 5 1, or alkyl can be prepared by deprotection of compound of formula 7.1 in which R 7 is H with a base followed by addition of an electrophilic agent as shown in Scheme 7. This reaction is carried out in suitable organic solvents such as THF, ether and the like and at temperature about -78 C. Base such as n-buthyl lithium can be used for the deprotonation. Electrophilic reagents such as bromine, iodine, 1 ,2- dibromo-tetrachloroethane, methyl iodide can be used.
  • a compound of formula 8.3 in which R 3 is Cl, Br, or I can be prepared by treating compounds of formula 8.1 or 8.4 in which R 3 is H with electrophilic agents such as N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS).
  • electrophilic agents such as N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS).
  • NBS N-bromosuccinimide
  • NCS N-chlorosuccinimide
  • N-iodosuccinimide N-iodosuccinimide
  • a compound of formula 8.3 in which R 3 is NO 2 can be prepared by treating compounds of formula 8.1 in which R 3 is H with nitrating agents such as fuming nitric acid, potassium nitrate or the like. The reaction can be carried out with suitable solvents such as sulfuric acid, acetic anhydride, trifluoroacetic acid and the like.
  • a compound of formula 9.2 with R 7 is NR 10 R 11 or OR 15 can be prepared by substitution of a compound 9.1 with R 7 is Br or Cl with an amine or alcohol in a suitable solvent such as DMF, DMA, NMP and the like. These reactions can be carried out at 120-200 C under conventional heating or under microwave conditions.
  • a compound of formula 10.2 with R 7 is CN, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted amino can be prepared by transition metal -mediated reactions of a compound with formula 10.1 with R 7 is Cl, Br, or I.
  • transition metal-mediated reactions can be one of those in the literature such as Suzuki-Miyaura reacions, Heck reactions, Stille reactions, Sonogashira reactions, and Buchwald aminations.
  • a compound of formula 10.4 with R 5 is CN, optionally substituted aryl, optionally substituted heteroaromatic rings, or optionally substituted amino can be prepared by transition metal-mediated reactions of a compound with formula 10.3 with R 5 is Cl, Br, or I.
  • transition metal -mediated reactions can be one of those in the literature such as Suzuki-Miyaura reacions, Heck reactions, Stille reactions, Sonogashira reactions, and Buchwal- Hartwig animations.
  • Substituted pyridines of formula 11.5 with R 7 is polyhalogenated alkyl, such as CF 3 , or CF 2 Cl, can be prepared using the Kr ⁇ hnke pyridine synthesis (F. Krohnke, Synthesis, 1976, 1- 24) by reacting a pyridinium salt of formula 11.4 and 4-substituted-2-oxo-but-3-enoic acid or its acid salt in the presence of ammonium acetate. The reaction can be carried out in suitable solvents such as methanol, acetic acid, water and the like and heating at 80-100 0 C maybe used.
  • suitable solvents such as methanol, acetic acid, water and the like and heating at 80-100 0 C maybe used.
  • Pyridinium salt of formula 11.4 in which R 7 is CF 2 Cl or CF 3 can be prepared by reacting 1 -carboxymethylpyridinium chloride 11.1 (T. Thorsteinsson, et al, J. Med. Chem. 2003, 46, 4173-4181) with anhydrides such as trifluoroacetic anhydride, dichlorofluoroacetic anhydride in the presence of a base.
  • a base such as N,N-diisopropylethylamine, or triethylamine can be used.
  • the reaction is carried out in suitable organic solvents, such as ether, THF or the like and at temperature around 0 0 C.
  • the betaeine of formula 11.3 can be hydrolyzed under acidic conditions to give Pyridinium salt of formula 11.4. Acids such as hydrochloric acid can be used and heating at 40-80 0 C may be used.
  • 4-Substituted-2-oxo-but-3-enoic acid can be obtained from commercial sources or can be prepared as known in the art.
  • Compounds with R 5 is furan-2-yl can be prepared by reacting 2-furaldehyde with pyruvic acid in the presence of base.
  • Suitable bases such as aqueous sodium hydroxide or aqueous potassium hydroxide can be used and temperature around 0 0 C may be used.
  • Substituted pyridine 2-carboxyaldehyde 11.6 can be prepared by conversion of pyridine 2-carboxylic acid 11.5 to an ester followed by reduction with hydride reagents such as lithium aluminum hydride (LAH), di-isobutylaluminum hydride (DIBAL-H) and the like.
  • LAH lithium aluminum hydride
  • DIBAL-H di-isobutylaluminum hydride
  • the reaction can be carried out in suitable solvents such Et 2 O, THF and the like and temperatures of from about -78 to 0 0 C may be used.
  • substituted pyridine 2-carboxyaldehyde 11.6 can be prepared by conversion of pyridine 2-carboxylic acid 11.5 to a Weinreb amide followed by reduction with hydride reagents such as lithium aluminum hydride (LAH), di- isobutylaluminum hydride (DIBAL-H) and the like. The reaction can be carried out in suitable solvents such Et 2 O, THF and the like and temperatures of from about -78 to 0 0 C may be used. [0194] Substituted pyridine 2-carboxyaldehyde 11.6 can react with an alkyl azido acetate 11.7 under basic condition to give substituted 2-azido-2-pyridine acrylate of formula 11.8.
  • hydride reagents such as lithium aluminum hydride (LAH), di- isobutylaluminum hydride (DIBAL-H) and the like.
  • LAH lithium aluminum hydride
  • DIBAL-H di- isobut
  • Suitable bases such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and the like can be used.
  • the reaction can be carried out in suitable solvents such as methanol, ethanol, iso- propanol, tert-butanol and the like and the temperatures of from about -50 to 0 0 C may be used.
  • Pyrazolo[l ,5-a]pyridines of formula 11.9 can be prepared by heating substituted 2- azido-2-pyridine acrylate of formula 11.8.
  • the reaction can be carried out in suitable solvents such as toluene, xylene, DMF, DMA, NMP and the like. These reactions can be carried out at 120-200 0 C under conventional heating or under microwave conditions.
  • Esters of pyrazolo[l,5-a]pyridines of formula 11.9 can be saponified under basic conditions such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.
  • the reaction can be carried out in suitable solvents such as THF, methanol and the like with the addition of water. These reactions can be carried out at room temperature or optionally with heating.
  • the acids obtained can be coupled with an amine NHR 10 R 1 ' or amine salt to give compounds of formula 11.10 under standard amide coupling conditions described above.
  • Scheme 12 describes the synthesis of imidazo[l,2-b]pyridazine analogs such as 12.6.
  • the appropriately substituted 2-chloropyridazine 12.1 can be aminated with ammonia in solvents such as iso-propanol to give 2-aminopyridazine 12.2 and the reaction is usually carried out under heating in a sealed tube.
  • 2-Chloropyridazine can in turn be prepared from chlorination of 2H- pyridazin-3-one with phosphoryl chloride and the like.
  • Substituted 2-aminopyridazine can be cyclized with substituted methyl bromopyruvate in solvents such as DMF and the like and at temperatures 50-80 0 C to give substituted imidazo[l,2-b]pyridazine 12.3.
  • Halogenation at the 3- position can be carried out by reacting imidazo[l,2-b]pyridazine 12.3 with N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like.
  • the methyl ester of substituted imidazo[l,2-b]pyridazine 12.4 can be saponified with bases such as lithium hydroxide, sodium hydroxide, and the like and in solvents such as tetrahydrofuran, alcohol, and water.
  • Substituted imidazo[l,2-b]pyridazine-2-carboxylic acids 12.5 can be converted to the amides 12.6 in the presence of a coupling agent such as benzotriazole-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP®), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP®), 2-( 1 H-benzotriazole- 1 -y I)- 1 , 1 ,3 ,3 -tetramethylaminium hexafluorophosphate (HBTU), O-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), or 1,3-dicyclohexylcarbodiimide (DCC) or l-(3-dimethylaminopropyl
  • a base such as N,N-diisopropylethylamine, triethylamine, or N- methylmorpholine can be used.
  • the reaction is carried out in suitable organic solvents, such as DMF, THF and the like.
  • suitable amines and amine salts are either commercially available or they can be prepared from commercial available starting materials by methods known in the art.
  • Scheme 13 describes the synthesis of benzimidazole analogs such as 13.7 and 13.8.
  • Benzimidazole scaffold can be assembled by cyclization of substituted 2-acyl-l,2- diaminophenediamine.
  • Substituted aniline 13.1 can be acylated with ethyl oxalyl chloride to give substituted N-phenyl-oxalamic acid ethyl ester 13.2 which in turn can be nitrated using nitric acid/sulfuric acid to give substituted N-(2-nitro-phenyl)-oxalamic acid ethyl ester 13.3.
  • Reduction of nitro group can be carried out using sodium dithionite or other reducing reagents.
  • 1 -alkyl- lH-benzimidazole derivatives can be prepared in Scheme 14.
  • N-alkylation of substituted N-(2-nitro-phenyl)-oxalamic acid ethyl ester 14.1 can be prepared with alkyl halides, alkyl mesylates, alkyl triflates or the like with suitable bases such as sodium hydride in solvents such as DMF, THF and the like.
  • Reduction of nitro group can be carried out using sodium dithionite or other reducing reagents.
  • Addition of aromatic or heteroaromatic groups with concomitant cyclication to benzimidazole and saponification of ethyl ester can be achieved under Suzuki coupling conditions.
  • the resultant substituted 1-alkyl-lH- benzoimidazole-2-carboxylic acids 14.4 can be converted to the amides 14.5 using standard coupling conditions as described above.
  • chemical entities possessing antiviral activity including against hepatitis C virus.
  • the chemical entities provided herein may inhibit viral replication by inhibiting the enzymes involved in replication, including RNA dependent RNA polymerase. They may also inhibit other enzymes utilized in the activity or proliferation of viruses in the flaviviridae family, such as HCV.
  • a daily dose ranges from about 0.05 to 100 mg/kg of body weight; in certain embodiments, from about 0.10 to 10.0 mg/kg of body weight, and in certain embodiments, from about 0.15 to 1.0 mg/kg of body weight.
  • the dosage range would be about from 3.5 to 7000 mg per day; in certain embodiments, about from 7.0 to 700.0 mg per day, and in certain embodiments, about from 10.0 to 100.0 mg per day.
  • the amount of the chemical entity administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician; for example, a likely dose range for oral administration would be from about 70 to 700 mg per day, whereas for intravenous administration a likely dose range would be from about 70 to 700 mg per day depending on compound pharmacokinetics.
  • Administration of the chemical entities described herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, sublingually, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly.
  • oral or parenteral administration is used.
  • compositions or formulations include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like.
  • the chemical entities can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • the chemical entities described herein can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like).
  • a conventional pharmaceutical carrier e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • the pharmaceutical composition will contain about 0.005% to 95%; in certain embodiments, about 0.5% to 50% by weight of a chemical entity.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • the chemical entities described herein can be co-administered with, and the pharmaceutical compositions can include, other medicinal agents, pharmaceutical agents, adjuvants, and the like.
  • suitable medicinal and pharmaceutical agents include therapeutically effective amounts of one or more agents active against HCV.
  • the agent active against HCV is an inhibitor of HCV proteases, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5 '-monophosphate dehydrogenase.
  • the agent active against HCV is an inhibitor of HCV proteases, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase.
  • Active agents against HCV include ribavirin, levovirin, viramidine, thymosin alpha- 1, an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, either alone or in combination with ribavirin or levovirin.
  • the additional agent active against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or levovirin.
  • the agent active against hepatitis C virus is interferon.
  • Suitable medicinal and pharmaceutical agents include TRH, diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, compounds disclosed in U.S. Patent No. 3,239,345 (e.g., zeranol), compounds disclosed in U.S. Patent No. 4,036,979 (e.g., sulbenox), peptides disclosed in U.S. Patent No. 4,411,890 growth hormone secretagogues such as GHRP-6, GHRP-I (disclosed in U.S. Patent No.
  • Still other suitable medicinal and pharmaceutical agents include estrogen, testosterone, selective estrogen receptor modulators, such as tamoxifen or raloxifene, other androgen receptor modulators, such as those disclosed in Edwards, J. P. et. al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et. al., J. Med. Chem., 42, 210-212 (1999), and progesterone receptor agonists ("PRA”), such as levonorgestrel, medroxyprogesterone acetate (MPA).
  • PRA progesterone receptor agonists
  • HIV and AIDS therapies such as indinavir sulfate, saquinavir, saquinavir mesylate, ritonavir, lamivudine, zidovudine, lamivudine/zidovudine combinations, zalcitabine, didanosine, stavudine, and megestrol acetate.
  • Still other suitable medicinal and pharmaceutical agents include antiresorptive agents, hormone replacement therapies, vitamin D analogues, elemental calcium and calcium supplements, cathepsin K inhibitors, MMP inhibitors, vitronectin receptor antagonists, Src SH.sub.2 antagonists, vacular — H + -ATPase inhibitors, ipriflavone, fluoride, Tibo lone, pro stanoids, 17-beta hydroxysteroid dehydrogenase inhibitors and Src kinase inhibitors.
  • compositions when employed in combination with the chemical entities described herein, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
  • the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
  • compositions The percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages. In certain embodiments, the composition will comprise from about 0.2 to 2% of the active agent in solution.
  • compositions of the chemical entities described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns.
  • the chemical entities provided will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of the chemical entity, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the chemical entity used, the route and form of administration, and other factors.
  • the drug can be administered more than once a day, such as once or twice a day.
  • Therapeutically effective amounts of the chemical entities described herein may range from approximately 0.05 to 50 mg per kilogram body weight of the recipient per day; such as about 0.0 1-25 mg/kg/day, for example, from about 0.5 to 10 mg/kg/day.
  • the dosage range may be about 35-70 mg per day.
  • the chemical entities will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • oral administration with a convenient daily dosage regimen that can be adjusted according to the degree of affliction may be used.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. Another manner for administering the provided chemical entities is inhalation.
  • the choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.
  • the chemical entity can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration.
  • suitable dispenser for administration There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI).
  • MDI metered dose inhalers
  • DPI dry powder inhalers
  • Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract.
  • MDF s typically are formulation packaged with a compressed gas.
  • the device Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
  • DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air- stream during breathing by the device.
  • the therapeutic agent In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose.
  • a measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
  • compositions have been developed for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nM in which the active material is supported on a cross-linked matrix of macromolecules.
  • U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of, in general, at least one chemical entity described herein in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the at least one chemical entity described herein.
  • excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Liquid carriers, for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a chemical entity described herein in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • the amount of the chemical entity in a composition can vary within the full range employed by those skilled in the art. Typically, the composition will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of at least one chemical entity described herein based on the total composition, with the balance being one or more suitable pharmaceutical excipients.
  • the at least one chemical entity described herein is present at a level of about 1-80 wt%. Representative pharmaceutical compositions containing at least one chemical entity described herein are described below.
  • the present specification is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one chemical entity described herein in combination with a therapeutically effective amount of another active agent against RNA- dependent RNA virus and, in particular, against HCV.
  • Agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1, an inhibitor of HCV NS3 serine protease, or an inhibitor of inosine monophosphate dehydrognease, interferon-a, pegylated interferon- ⁇ (peginterferon-a), a combination of interferon-a and ribavirin, a combination of peginterferon-a and ribavirin, a combination of interferon-a and levovirin, and a combination of peginterferon-a and levovirin.
  • Interferon-a includes, but is not limited to, recombinant interferon- a2a (such as ROFERON interferon available from Hoffman-LaRoche, Nutley, NJ), interferon- a2b (such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA), a consensus interferon, and a purified interferon-a product.
  • interferon- a2a such as ROFERON interferon available from Hoffman-LaRoche, Nutley, NJ
  • interferon- a2b such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA
  • a consensus interferon such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA
  • Step 1 l-Amino-4-phenyl-pyridinium 2,4-dinitro-phenolate [0227] A mixture of 4-phenyl pyridine (1.55 g, 10 mmol) and 2,4-dinitro-phenyl- hydroxylamine (2.86 g, 11.5 mmol) was stirred in acetonitrile (15 mL) at 45 0 C for 12.5 hours. Upon cooling, the mixture was triturated with diethyl ether (50 mL) and centrifuged to give a solid.
  • Step 2 5-Phenyl-pyrazolo[l,5-a]pyridine-2,3-dicarboxylic acid dimethyl ester
  • Step 4 7-Iodo-5-phenyl-pyrazolo[l,5-a]pyridine-2-carboxylic acid and 3,7-diiodo-5-phenyI- pyrazolo[l,5-a]pyridine-2-carboxylic acid [0230] To a solution of 5-phenyl-pyrazolo[l,5-a]pyridine-2-carboxylic acid (600 mg, 2.52 mmol) in THF (35 mL) at -78 0 C was added dropwise a solution of n-butyl lithium (2.5 M in hexanes, 2.22 mL, 5.54 mmol) over 5 min.
  • Step 1 3-Nitro-6-phenyl-4-trifluoromethyl-pyridin-2-ylamine (ref: D.G. Batt, G.C.Houghton, J. Het. Chem., 1995, 32,963)
  • Step 2 S-Chloro-V-trifluoromethyl-lH-indoIe ⁇ -carboxylic acid methyl ester
  • H 2 SO 4 (0.5 mL) was heated under refux in MeOH (60 mL). After 16 hours, extra cone. H 2 SO 4 (0.5 mL) and MeOH (25 mL) were added. After 2 hours, the solvent was removed and diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO 3 (50 mL), then brine (50 mL).
  • Step 3 S-Chloro-S-iodo-V-trifluoromethyl-lH-indole-Z-carboxylic acid methyl ester
  • Step 1 5-Bromo-7-chloro-lH-indole-2-carboxylic acid (thiophen-2-ylmethyl)-amide
  • Example 12 7-Bromo-3-chloro-5-phenyl-pyrazolo[l,5-a]pyridine-2-carboxylic acid (thiophen-2- ylmethyl)-amide (Compound 112) [0252] A solution of 7-bromo-5 -phenyl-pyrazolo [1,5 -a]pyridine-2-carboxylic acid (thiophen- 2-ylmethyl)-amide (36.8 mg, 0.0893 mmol) and NCS (14.3 mg, 0.107 mmol) was stirred in DMF (1 mL) at 50 0 C for 4 hours.
  • Step 4 6-(Chloro-difluoro-methyl)-4-furan-2-yl-pyridine-2-carboxylic acid
  • a suspension of chlorodifluoromethylacylpyridinium chloride (9.02 g, 34.68 mmol), (£)-4-furan-2-yl-2-oxo-but-3-enoic acid (5.76 g, 34.68 mmol) and ammonium acetate (21.4 g, 277.5 mmol) was heated in water (50 mL) at 95 0 C for 8.5 hours. The mixture was cooled and extracted with EtOAc (200 mL, 2 x 100 mL), dried (MgSO 4 ), filtered and concentrated.
  • Step 6 6-(ChIo ro-difluoro-methy l)-4-furan-2-yl-py ridine-2-carbaldehy de
  • 6-(chloro-difluoro-methyl)-4-ruran-2-yl-pyridine-2-carboxylic acid methoxy-methyl-amide (2.97 g, 9.39 mmol) in THF (70 mL) at - 78 0 C was added dropwise a solution of diisobutylaluminum hydride (DIBAL-H, IM in THF) (16.9 mL, 16.9 mmol).
  • DIBAL-H diisobutylaluminum hydride
  • Step 7 (Zj-Z-Azido-S-f ⁇ chloro-difluoro-methyl ⁇ -furan-Z-yl-pyridin-l-yll-acrylic acid ethyl ester
  • Step 9 7-(Chloro-difluoro-methyl)-5-furan-2-yl-pyrazolo[l,5-a]pyridine-2-carboxylic acid (thiophen-2-ylmethyl)-amide (Compound 133)
  • Step 2 ⁇ -Bromo-S-trifluoromethyl-imidazoIl ⁇ -alpyridine ⁇ -carboxylic acid ethyl ester
  • a mixture of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (21.78 g, 90.37 mmol) and ethyl bromopyruvate (90% pure, 25.3 mL, 180.74 mmol) was heated in DMF (180 mL) at 50 0 C for 1 day. Upon cooling, the solvent was removed to half the volume under reduced pressure. The mixture was diluted with EtOAc (500 mL) and washed with water (3 x 150 mL), dried (Na 2 SO 4 ), filtered and concentrated.
  • the mixture was partitioned between ethyl acetate and water and the organic layer was dried (MgSO 4 ) to afford the crude product.
  • the product was purified by passing through a short silica column to afford 6-phenyl-8-trifluoromethyl- imidazo[l,2-a]pyridine-2-carboxylic acid (thiophen-2-ylmethyl)-amide (0.058 gm, 60%) as a white solid.
  • Step 1 l-Amino-4-bromo-2-chloro-pyridinium mesitylenesulfonate
  • 4-bromo-2-chloropyridine 2.048 g, 10.64 mmol
  • CH 2 Cl 2 5 mL
  • 0-mesitylsulfonylhydroxylamine MSH, 2.52 g, 11.71 mmol
  • the solvent was concentrated and triturated with Et 2 O to give a white syrup.
  • the solvent was decanted and triturated again with Et 2 O.
  • the product was dried under vacuum to give 1-amino- 4-bromo-2-chloro-pyridinium mesitylenesulfonate (3.16 g, 73%).
  • Step 2 5-Bromo-7-chloro-pyrazolo[l,5-a]pyridine-2,3-dicarboxylic acid dimethyl ester
  • 1 -amino-4-bromo-2-chloro-pyridinium mesitylenesulfonate 3.16 g, 7.75 mmol
  • K 2 CO 3 3.21 g, 23.25 mmol
  • dimethyl acetylenedicarboxylate 1.43 mL, 11.63 mmol
  • Step 4 5-Bromo-7-chloro-pyrazolo[l,5-a]pyridine-2-carboxylic acid (thiophen-2-ylmethyl)- amide
  • Step 5 7-Chloro-5-phenyl-pyrazolo[l,5-a]pyridine-2-carboxylic acid (thiophen-2- ylmethyl)-amide (Compound 144)
  • Step 1 ⁇ -Bromo-S-chloro-S-trifluoromethyl-imidazofl ⁇ -aJpyridine-l-carboxylic acid ethyl ester
  • Step 2 ⁇ -Bromo-S-chloro-S-trifluoromethyl-imidazofl ⁇ -alpyridine-Z-carboxylic acid
  • Step 3 ⁇ -Bromo-S-chloro-S-trifluoromethyl-imidazofl ⁇ -aJpyridine-Z-carboxylic acid (thiophen-2-ylmethyl)-amide (Compound 151)
  • Example 53 7-Methylamino-5-phenyl-pyrazolo[l,5-a]pyridine-2-carboxylic acid (thiophen-2-ylmethyl)- amide (Compound 153) [0322] 7-Chloro-5-phenyl-pyrazolo[l,5-a]pyridine-2-carboxylic acid (thiophen-2-ylmethyl)- amide (50 mg) was treated with methylamine (2M in THF) and heated at 120 0 C to give 7- methylamino-5-phenyl-pyrazolo[l ,5-a]pyridine-2-carboxylic acid (thiophen-2-ylmethyl)-amide (34.2 mg) after column chromatography.
  • Step 2 6-Furan-2-yl-3-methyl-8-trifluoromethyl-imidazo[l,2-a]pyridine-2-carboxylic acid (thiophen-2-ylmethyl)-amide (Compound 156)
  • Step 2 S-Chloro-o-furan-l-yl-S-trifluoromethyl-imidazoIl ⁇ -alpyridine-l-carboxylic acid
  • Step 3 S-Chloro- ⁇ -furan ⁇ -yl-S-trifluoromethyl-imidazofljZ-ajpyridine-l-carboxylic acid (furan-2-ylmethyl)-amide (Compound 158)
  • Example 72 S-Chloro- ⁇ -furan ⁇ -yl-S-trifluoromethyl-imidazoIl ⁇ -alpyridine ⁇ -carboxylic acid [(2- dimethylamino-ethy lcarbamoyl)-thiophen-2-y 1-methy 1] -amide (Compound 172) [0355] [(3-Chloro-6-furan-2-yl-8-trifluoromethyl-imidazo[l,2-a]pyridine-2-carbonyl)- amino]-thiophen-2-yl-acetic acid was coupled to N, N-dimethylethylenediamine under standard amide bond coupling conditions to give 3-chloro-6-furan-2-yl-8-trifluoromethyl-imidazo[l,2- a]pyridine-2-carboxylic acid [(2-dimethylamino-ethylcarbamoyl)-thiophen-2-yl-methyl]-amide.

Abstract

La présente invention concerne certaines entités chimiques, compositions pharmaceutiques, et des procédés pour traiter un membre de la famille des virus flaviviradae tel que l'hépacivirus (Hépatite C ou VHC).
PCT/US2008/009606 2007-08-10 2008-08-08 Entités chimiques bicycliques azotées pour traiter les infections virales WO2009023179A2 (fr)

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CN200880111116A CN101842098A (zh) 2007-08-10 2008-08-08 用于治疗病毒感染的含氮的二环化学实体
US12/672,942 US20120121540A1 (en) 2007-08-10 2008-08-08 Certain Nitrogen Containing Bicyclic Chemical Entities For Treating Viral Infections
MX2010001650A MX2010001650A (es) 2007-08-10 2008-08-08 Entidades quimicas biciclicas que contienen nitrogeno para el tratamiento de infecciones virales.
CA2695989A CA2695989A1 (fr) 2007-08-10 2008-08-08 Entites chimiques bicycliques azotees pour traiter les infections virales
BRPI0814939-9A2A BRPI0814939A2 (pt) 2007-08-10 2008-08-08 Entidade química, composição farmacêutica, e, método para tratar uma infecção viral em um mamífero.
EP08795214A EP2187883A2 (fr) 2007-08-10 2008-08-08 Entités chimiques bicycliques azotées pour traiter les infections virales
JP2010519999A JP2010535773A (ja) 2007-08-10 2008-08-08 ウイルス感染を治療するための窒素含有二環式化学物質
EA201000201A EA201000201A1 (ru) 2007-08-10 2008-08-08 Азотсодержащие бициклические химические вещества для лечения вирусных инфекций
AU2008287421A AU2008287421A1 (en) 2007-08-10 2008-08-08 Nitrogen containing bicyclic chemical entities for treating viral infections
ZA2010/01523A ZA201001523B (en) 2007-08-10 2010-03-02 Nitrogen containing bicyclic chemical entities for treating viral infections

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Cited By (128)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009112651A1 (fr) * 2008-01-02 2009-09-17 Sanofi-Aventis Dérivés d'mtoazo[1,2-a]pyridine-2-carboxamides, leur préparation et leur application en thérapeutique
WO2010032195A1 (fr) * 2008-09-16 2010-03-25 Csir Imidazopyridines et imidazopyrimidines utilisés comme inhibiteurs de la transcriptase inverse du vih-1
WO2011041713A2 (fr) * 2009-10-02 2011-04-07 Glaxosmithkline Llc Agents anti-viraux à base de pipérazinyle
WO2011058766A1 (fr) * 2009-11-16 2011-05-19 Raqualia Pharma Inc. Dérivés d'arylcarboxamide comme bloqueurs de ttx-s
WO2011097491A1 (fr) * 2010-02-04 2011-08-11 Glaxosmithkline Llc Agents antiviraux à base de benzimidazole
WO2012008508A1 (fr) * 2010-07-14 2012-01-19 武田薬品工業株式会社 Composé hétérocyclique
US8133897B2 (en) 2008-06-20 2012-03-13 H. Lundbeck A/S Phenylimidazole derivatives as PDE10A enzyme inhibitors
US8242125B2 (en) 2008-12-09 2012-08-14 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
WO2012119984A1 (fr) 2011-03-09 2012-09-13 Bayer Cropscience Ag Amides d'acide carboxylique d'indole et de benzimidazole utilisés comme insecticides et acaricides
WO2012143796A2 (fr) * 2011-04-21 2012-10-26 Institut Pasteur Korea Composés anti-inflammatoires
WO2013025992A1 (fr) 2011-08-17 2013-02-21 Glaxosmithkline Llc Procédés thérapeutiques
WO2012072713A3 (fr) * 2010-11-30 2013-04-04 Oryzon Genomics, S.A. Inhibiteurs de la déméthylase spécifique de la lysine pour des maladies et troubles liés aux flaviviridés
US8455522B2 (en) 2009-05-15 2013-06-04 Novartis Ag Benzoxazolone derivatives as aldosterone synthase inhibitors
JP2013522191A (ja) * 2010-03-10 2013-06-13 ブリストル−マイヤーズ スクイブ カンパニー Ｃ型肝炎の処置のための化合物
US8501936B2 (en) 2009-06-05 2013-08-06 Cephalon, Inc. Preparation and uses of 1,2,4-triazolo [1,5a] pyridine derivatives
US8524717B2 (en) 2008-10-17 2013-09-03 Oryzon Genomics, S.A. Oxidase inhibitors and their use
WO2014026984A1 (fr) 2012-08-17 2014-02-20 Bayer Cropscience Ag Amides d'acide azaindole-carboxylique et thiocarboxylique comme insecticides et acaricides
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8748435B2 (en) 2011-04-01 2014-06-10 Novartis Ag Pyrazolo pyrimidine derivatives
US8778972B2 (en) 2009-05-15 2014-07-15 Novartis Ag 5-pyridin-3-yl-1, 3-dihydro-indol-2-on derivatives and their use as modulators of aldosterone synthase and/or CYP11B1
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
WO2014133008A1 (fr) 2013-02-27 2014-09-04 塩野義製薬株式会社 Dérivés d'indole et d'azaindole ayant chacun une activité d'activation d'ampk
US8841297B2 (en) 2008-06-20 2014-09-23 H. Lundbeck A/S Phenylimidazole derivative as PDE10A enzyme inhibitor
US8859555B2 (en) 2009-09-25 2014-10-14 Oryzon Genomics S.A. Lysine Specific Demethylase-1 inhibitors and their use
US8946296B2 (en) 2009-10-09 2015-02-03 Oryzon Genomics S.A. Substituted heteroaryl- and aryl-cyclopropylamine acetamides and their use
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US8993808B2 (en) 2009-01-21 2015-03-31 Oryzon Genomics, S.A. Phenylcyclopropylamine derivatives and their medical use
US9006449B2 (en) 2010-07-29 2015-04-14 Oryzon Genomics, S.A. Cyclopropylamine derivatives useful as LSD1 inhibitors
US9061966B2 (en) 2010-10-08 2015-06-23 Oryzon Genomics S.A. Cyclopropylamine inhibitors of oxidases
US9090661B2 (en) 2009-03-27 2015-07-28 Merck Sharp & Dohme Corp. Inhibitors of hepatitis C virus replication
US9149447B2 (en) 2010-04-19 2015-10-06 Oryzon Genomics S.A. Lysine specific demethylase-1 inhibitors and their use
US9181198B2 (en) 2010-07-29 2015-11-10 Oryzon Genomics S.A. Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use
WO2015169776A1 (fr) 2014-05-08 2015-11-12 Bayer Cropscience Ag Sulfonamides de pyrazolopyridine en tant que nématicides
US9186337B2 (en) 2010-02-24 2015-11-17 Oryzon Genomics S.A. Lysine demethylase inhibitors for diseases and disorders associated with Hepadnaviridae
US9254292B2 (en) 2010-09-29 2016-02-09 Merck Sharp & Dohme Corp. Fused tetracycle derivatives and methods of use thereof for the treatment of viral diseases
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US9381191B2 (en) 2012-07-20 2016-07-05 Metabrain Research Imidazopyridine derivatives useful in treating diabetes
US9422250B2 (en) 2011-04-08 2016-08-23 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US9428512B2 (en) 2012-11-20 2016-08-30 Glaxosmithkline Llc Compounds
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
WO2016162318A1 (fr) * 2015-04-08 2016-10-13 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycles bicycliques condensés utilisés en tant que produits de lutte antiparasitaire, et leurs produits intermédiaires
US9469597B2 (en) 2011-10-20 2016-10-18 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US9487512B2 (en) 2011-10-20 2016-11-08 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US9493450B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493442B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9504690B2 (en) 2011-03-17 2016-11-29 Merck Sharp & Dohme Corp. Tetracyclic xanthene derivatives and methods of use thereof for the treatment of viral diseases
US9518064B2 (en) 2012-04-26 2016-12-13 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyridazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9540383B2 (en) 2012-11-20 2017-01-10 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9550785B2 (en) 2012-11-20 2017-01-24 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9555036B2 (en) 2012-08-24 2017-01-31 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US9555038B2 (en) 2013-01-16 2017-01-31 Merck Sharp & Dohme Corp. Heterocycle-substituted tetracyclic compounds and methods of use thereof for the treatment of viral diseases
US9598419B1 (en) 2014-06-24 2017-03-21 Universite De Montreal Imidazotriazine and imidazodiazine compounds
US9616058B2 (en) 2010-02-24 2017-04-11 Oryzon Genomics, S.A. Potent selective LSD1 inhibitors and dual LSD1/MAO-B inhibitors for antiviral use
US9617279B1 (en) 2014-06-24 2017-04-11 Bristol-Myers Squibb Company Imidazooxadiazole compounds
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
WO2017093180A1 (fr) 2015-12-01 2017-06-08 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycles bicycliques condensés utilisés en tant que produits de lutte antiparasitaire
US9688695B2 (en) 2012-04-26 2017-06-27 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
JP2017141271A (ja) * 2009-08-17 2017-08-17 インテリカイン， エルエルシー 複素環式化合物およびそれらの使用
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
EP3241830A1 (fr) 2016-05-04 2017-11-08 Bayer CropScience Aktiengesellschaft Derivés de bicycles condensés hétérocycliques utilisés comme pesticides
US9822130B2 (en) 2014-11-21 2017-11-21 Merck Sharp & Dohme Corp. Triazolo-pyrazinyl derivatives useful as soluble guanylate cyclase activators
US9862730B2 (en) 2012-04-26 2018-01-09 Bristol-Myers Squibb Company Imidazothiadiazole derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
US9877968B2 (en) 2008-08-11 2018-01-30 Glaxosmithkline Llc 6-amino-purin-8-one compounds
WO2018033455A1 (fr) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
US9908859B2 (en) 2011-02-08 2018-03-06 Oryzon Genomics, S.A. Lysine demethylase inhibitors for myeloproliferative disorders
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US9969687B2 (en) 2013-12-23 2018-05-15 Norgine B.V. Compounds useful as CCR9 modulators
WO2018130437A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2018130443A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
US10100027B2 (en) 2014-09-26 2018-10-16 Changzhou Yinsheng Pharmaceutical Co., Ltd. Benzofuran analogue as NS4B inhibitor
US10112946B2 (en) 2011-07-22 2018-10-30 Glaxosmithkline Llc Composition
US10118930B2 (en) 2014-11-03 2018-11-06 Bayer Pharma Aktiengesellschaft Piperidinylpyrazolopyrimidinones and their use
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
US10208048B2 (en) 2015-04-28 2019-02-19 Janssen Sciences Ireland Uc RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
WO2019054427A1 (fr) 2017-09-14 2019-03-21 第一三共株式会社 Composé à structure cyclique
US10253003B2 (en) 2012-11-16 2019-04-09 Janssen Sciences Ireland Uc Heterocyclic substituted 2-amino quinazoline derivatives for the treatment of viral infections
WO2019068572A1 (fr) 2017-10-04 2019-04-11 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
US10259793B2 (en) 2013-02-21 2019-04-16 Janssen Sciences Ireland Uc 2-aminopyrimidine derivatives for the treatment of viral infections
US10259814B2 (en) 2012-10-10 2019-04-16 Janssen Sciences Ireland Uc Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US10266543B2 (en) 2013-03-29 2019-04-23 Janssen Sciences Ireland Uc Macrocyclic deaza-purinones for the treatment of viral infections
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10280180B2 (en) 2012-07-13 2019-05-07 Janssen Sciences Ireland Uc Macrocyclic purines for the treatment of viral infections
US10280167B2 (en) 2011-11-09 2019-05-07 Janssen Sciences Ireland Uc Purine derivatives for the treatment of viral infections
US10316043B2 (en) 2013-07-30 2019-06-11 Janssen Sciences Ireland Unlimited Company Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections
US10329255B2 (en) 2015-08-12 2019-06-25 Incyte Corporation Salts of an LSD1 inhibitor
US10377738B2 (en) 2013-05-24 2019-08-13 Janssen Sciences Ireland Unlimited Company Pyridone derivatives for the treatment of viral infections and further diseases
US10385054B2 (en) 2013-06-27 2019-08-20 Janssen Sciences Ireland Unlimited Company Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
WO2019162174A1 (fr) 2018-02-21 2019-08-29 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2019175046A1 (fr) 2018-03-12 2019-09-19 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
WO2019201921A1 (fr) 2018-04-20 2019-10-24 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2019219517A1 (fr) 2018-05-17 2019-11-21 Bayer Aktiengesellschaft Dérivés de dihydropyrazolo pyrazine carboxamide substitués
US10696666B2 (en) 2016-10-18 2020-06-30 CellCentric Limited Pharmaceutical compounds
US10730874B2 (en) 2018-03-13 2020-08-04 Shire Human Genetic Therapies, Inc. Inhibitors of plasma kallikrein and uses thereof
US10968184B2 (en) 2016-09-29 2021-04-06 Janssen Sciences Ireland Unlimited Company Pyrimidine prodrugs for the treatment of viral infections and further diseases
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US11053256B2 (en) 2016-07-01 2021-07-06 Janssen Sciences Ireland Unlimited Company Dihydropyranopyrimidines for the treatment of viral infections
US11053243B2 (en) 2009-03-27 2021-07-06 Merck Sharp & Dohme Corp. Inhibitors of hepatitis C virus replication
AU2016363937B2 (en) * 2015-11-30 2021-07-08 Oxford University Innovation Limited Inhibitors of metallo-beta-lactamases
US11161850B2 (en) 2018-07-05 2021-11-02 Incyte Corporation Fused pyrazine derivatives as A2A / A2B inhibitors
US11168089B2 (en) 2018-05-18 2021-11-09 Incyte Corporation Fused pyrimidine derivatives as A2A / A2B inhibitors
US11306088B2 (en) 2016-06-21 2022-04-19 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
WO2022087422A1 (fr) * 2020-10-22 2022-04-28 Chulalongkorn University Dérivés pyrrolidine-3-carboxamide et utilisations de ces derniers
US11332470B2 (en) 2016-06-21 2022-05-17 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US11339165B2 (en) 2017-11-29 2022-05-24 Janssen Sciences Ireland Unlimited Company Pyrazolopyrimidines having activity against the respiratory syncytial virus (RSV)
US11370803B2 (en) 2019-09-18 2022-06-28 Takeda Pharmaceutical Company Limited Heteroaryl plasma kallikrein inhibitors
US11390624B2 (en) 2019-01-29 2022-07-19 Incyte Corporation Pyrazolopyridines and triazolopyridines as A2A / A2B inhibitors
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11453662B2 (en) 2018-04-18 2022-09-27 Cellcentric Ltd Process for preparing modulators of p300 and/or CBP
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11484597B2 (en) 2019-09-19 2022-11-01 Totus Medicines Inc. Therapeutic conjugates
US11491157B2 (en) 2018-01-31 2022-11-08 Janssen Sciences Ireland Unlimited Company Co Cork, IE Cycloalkyl substituted pyrazolopyrimidines having activity against RSV
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US11597704B2 (en) 2018-03-01 2023-03-07 Janssen Sciences Ireland Unlimited Company 2,4-diaminoquinazoline derivatives and medical uses thereof
WO2023057394A1 (fr) 2021-10-04 2023-04-13 Forx Therapeutics Ag Dérivés de n,n-diméthyl-4-(7-(n-(1-méthylcyclopropyl)sulfamoyl)-imidazo[1,5-a]pyridin-5-yl)pipérazine-1-carboxamide et dérivés correspondants de pyrazolo[1,5-a]pyridine utilisés en tant qu'inhibiteurs de parg pour le traitement du cancer
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11673894B2 (en) 2018-02-27 2023-06-13 Incyte Corporation Imidazopyrimidines and triazolopyrimidines as A2A / A2B inhibitors
US11708369B2 (en) 2018-04-23 2023-07-25 Janssen Sciences Ireland Unlimited Company Heteroaromatic compounds having activity against RSV
US11787796B2 (en) 2019-09-18 2023-10-17 Takeda Pharmaceutical Company Limited Plasma Kallikrein inhibitors and uses thereof
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100204265A1 (en) * 2009-02-09 2010-08-12 Genelabs Technologies, Inc. Certain Nitrogen Containing Bicyclic Chemical Entities for Treating Viral Infections
WO2011050284A1 (fr) * 2009-10-23 2011-04-28 Glaxosmithkline Llc Agents antiviraux de pyrazolylpyridine
US20120220581A1 (en) 2009-10-30 2012-08-30 Janssen-Cilag, S.A. IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10 INHIBITORS
AR080754A1 (es) 2010-03-09 2012-05-09 Janssen Pharmaceutica Nv Derivados de imidazo (1,2-a) pirazina y su uso como inhibidores de pde10
WO2012058125A1 (fr) 2010-10-26 2012-05-03 Presidio Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c
US10953012B2 (en) 2011-04-26 2021-03-23 Bioenergenix Llc Heterocyclic compounds for the inhibition of pask
WO2013000924A1 (fr) 2011-06-27 2013-01-03 Janssen Pharmaceutica Nv Dérivés de 1-aryl-4-méthyl-[1,2,4]triazolo[4,3-a]quinoxaline
WO2013100018A1 (fr) * 2011-12-28 2013-07-04 武田薬品工業株式会社 Composé hétérocyclique
RU2657540C2 (ru) 2012-06-26 2018-06-14 Янссен Фармацевтика Нв Комбинации, содержащие ингибиторы pde 2, такие как 1-арил-4-метил-[1,2,4]триазоло[4,3-а]хиноксалиновые соединения, и ингибиторы pde 10, для применения в лечении неврологических или метаболических расстройств
CA2875057C (fr) 2012-07-09 2021-07-13 Janssen Pharmaceutica Nv Composes d'imidazo (1,2-b) pyridazine et d'imidazo (1,2-a) pyrazine et leur utilisation en tant qu'inhibiteurs de la phosphodiesterase 10
WO2014066795A1 (fr) 2012-10-25 2014-05-01 Bioenergenix Composés hétérocycliques pour l'inhibition de pask
WO2014066743A1 (fr) 2012-10-25 2014-05-01 Bioenergenix Composés hétérocycliques pour l'inhibition de pask
JP6284490B2 (ja) * 2012-12-28 2018-02-28 株式会社新日本科学 イミダゾピリジン誘導体を有効成分として含むｏｃｔ３活性阻害剤又はｏｃｔ３検出剤
CN105121439A (zh) 2013-02-19 2015-12-02 辉瑞公司 作为pde4亚型抑制剂用于治疗cns和其他病症的氮杂苯并咪唑化合物
TWI530499B (zh) 2013-03-28 2016-04-21 吉李德科學股份有限公司 作為溴結構域（ｂｒｏｍｏｄｏｍａｉｎ）抑制劑之苯並咪唑酮衍生物類
TWI527811B (zh) 2013-05-09 2016-04-01 吉李德科學股份有限公司 作爲溴結構域抑制劑的苯並咪唑衍生物
US9193736B2 (en) 2013-06-11 2015-11-24 Janssen Pharmaceutica, Nv PDE 10a inhibitors for the treatment of type II diabetes
WO2014200885A1 (fr) 2013-06-11 2014-12-18 Janssen Pharmaceutica Nv Inhibiteurs de pde10a dans le traitement du diabète de type ii
US9453002B2 (en) 2013-08-16 2016-09-27 Janssen Pharmaceutica Nv Substituted imidazoles as N-type calcium channel blockers
UA115388C2 (uk) 2013-11-21 2017-10-25 Пфайзер Інк. 2,6-заміщені пуринові похідні та їх застосування в лікуванні проліферативних захворювань
US9108953B2 (en) 2013-11-26 2015-08-18 Gilead Sciences, Inc. Quinoline derivatives as bromodomain inhibitors
JP6713982B2 (ja) 2014-07-24 2020-06-24 ファイザー・インク ピラゾロピリミジン化合物
PE20170295A1 (es) 2014-08-06 2017-03-30 Pfizer Compuestos de imidazopiridazina
JP2018076234A (ja) * 2015-03-16 2018-05-17 大正製薬株式会社 ピラゾロ［１，５−ａ］ピリミジン化合物
US10233186B2 (en) 2016-04-15 2019-03-19 Blueprint Medicines Corporation Inhibitors of activin receptor-like kinase
WO2018013430A2 (fr) 2016-07-12 2018-01-18 Arisan Therapeutics Inc. Composés hétérocycliques pour le traitement d'une infection à arenavirus
WO2019079649A1 (fr) 2017-10-18 2019-04-25 Blueprint Medicines Corporation Pyrrolopyridines substituées utilisées en tant qu'inhibiteurs de la kinase apparentée au récepteur de l'activine
CN111518102B (zh) * 2019-05-14 2023-09-05 南京工业大学 环基甲酰及环基酮类化合物及其制备方法和药学上的用途
TW202204350A (zh) 2020-05-06 2022-02-01 美商雅捷可斯治療公司 作為ｊａｋ２抑制劑之６－雜芳基氧基苯并咪唑及氮雜苯并咪唑
WO2022076975A1 (fr) 2020-10-05 2022-04-14 Enliven Therapeutics, Inc. Composés de 5- et 6-azaindole pour l'inhibition de tyrosine kinases bcr-abl
WO2023086319A1 (fr) 2021-11-09 2023-05-19 Ajax Therapeutics, Inc. 6-hetero-aryloxy-benzimidazoles et azabenzimidazoles en tant qu'inhibiteurs de jak2
CN117402156A (zh) * 2022-07-08 2024-01-16 中国科学院上海药物研究所 一类酰胺化合物及其制备方法、药物组合物和用途

Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6060478A (en) * 1996-07-24 2000-05-09 Dupont Pharmaceuticals Azolo triazines and pyrimidines
US20020002145A1 (en) * 2000-02-10 2002-01-03 Cronstein Bruce N. Adenosine A2A receptor antagonists for treating and preventing hepatic fibrosis, cirrhosis and fatty liver
WO2003026589A2 (fr) * 2001-09-28 2003-04-03 Idenix (Cayman) Limited Procedes et compositions pour le traitement du virus de l'hepatite c au moyen de nucleosides modifies en 4'
WO2004074270A2 (fr) * 2003-02-21 2004-09-02 Pfizer Inc. Inhibiteurs de l'arn polymerase arn-dependante du virus de l'hepatite c, et compositions et traitements faisant appel a cet inhibiteur
WO2004087714A1 (fr) * 2003-04-04 2004-10-14 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Acetamides d'indole comme inhibiteurs de la polymerase ns5b du virus de l'hepatite c
WO2005009997A1 (fr) * 2003-07-30 2005-02-03 Pfizer Inc. Composes d'indazole 3,5 disubstitutes, compositions pharmaceutiques, et procedes pour medier ou inhiber la proliferation cellulaire
US20050175535A1 (en) * 2000-02-23 2005-08-11 Cv Therapeutics, Inc. Myocardial perfusion imaging method
US20050203128A1 (en) * 2004-03-13 2005-09-15 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
WO2006019831A1 (fr) * 2004-07-14 2006-02-23 Ptc Therapeutics, Inc. Procedes pour le traitement de l'hepatite c
WO2006036816A2 (fr) * 2004-09-24 2006-04-06 Smithkline Beecham Corporation Composes chimiques
WO2006054143A1 (fr) * 2004-11-17 2006-05-26 Pfizer Inc. Formes polymorphes de {5-[3-(4,6-difluoro-1h-benzimidazol-2-yl)-1h-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-ethyl-amine
WO2006091858A1 (fr) * 2005-02-25 2006-08-31 Rigel Pharmaceuticals, Inc. Benzisothiazoles utiles dans le traitement ou la prevention de l'infection a vhc
WO2006109633A1 (fr) * 2005-04-07 2006-10-19 Daiichi Sankyo Company, Limited Composé indole substitué
WO2007023381A1 (fr) * 2005-08-24 2007-03-01 Pfizer Inc. Methodes servant a preparer des inhibiteurs de hcv polymerase
WO2007071434A1 (fr) * 2005-12-22 2007-06-28 Smithkline Beecham Corporation Composes antiviraux contenant du 2-carboxy-thiophene
WO2007076286A2 (fr) * 2005-12-16 2007-07-05 Smithkline Beecham Corporation Composes chimiques
WO2007076228A2 (fr) * 2005-12-20 2007-07-05 Boehringer Ingelheim International Gmbh Inhibiteurs de kinases tec
WO2007117401A2 (fr) * 2006-04-07 2007-10-18 Janssen Pharmaceutica N.V. Indoles et benzoimidazoles modulateurs du récepteur de l'histamine h4
WO2008055808A1 (fr) * 2006-11-09 2008-05-15 F. Hoffmann-La Roche Ag Dérivés d'indole et de benzofuran 2-carboxamide

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3239345A (en) * 1965-02-15 1966-03-08 Estrogenic compounds and animal growth promoters
US4411890A (en) * 1981-04-14 1983-10-25 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
JPS5229318B2 (fr) * 1972-03-30 1977-08-01
US4036979A (en) * 1974-01-25 1977-07-19 American Cyanamid Company Compositions containing 4,5,6,7-tetrahydrobenz[b]thien-4-yl-ureas or derivatives and methods of enhancing growth rate
US4107288A (en) * 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5738985A (en) * 1993-04-02 1998-04-14 Ribogene, Inc. Method for selective inactivation of viral replication

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6060478A (en) * 1996-07-24 2000-05-09 Dupont Pharmaceuticals Azolo triazines and pyrimidines
US20020002145A1 (en) * 2000-02-10 2002-01-03 Cronstein Bruce N. Adenosine A2A receptor antagonists for treating and preventing hepatic fibrosis, cirrhosis and fatty liver
US20050175535A1 (en) * 2000-02-23 2005-08-11 Cv Therapeutics, Inc. Myocardial perfusion imaging method
WO2003026589A2 (fr) * 2001-09-28 2003-04-03 Idenix (Cayman) Limited Procedes et compositions pour le traitement du virus de l'hepatite c au moyen de nucleosides modifies en 4'
WO2004074270A2 (fr) * 2003-02-21 2004-09-02 Pfizer Inc. Inhibiteurs de l'arn polymerase arn-dependante du virus de l'hepatite c, et compositions et traitements faisant appel a cet inhibiteur
WO2004087714A1 (fr) * 2003-04-04 2004-10-14 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Acetamides d'indole comme inhibiteurs de la polymerase ns5b du virus de l'hepatite c
WO2005009997A1 (fr) * 2003-07-30 2005-02-03 Pfizer Inc. Composes d'indazole 3,5 disubstitutes, compositions pharmaceutiques, et procedes pour medier ou inhiber la proliferation cellulaire
US20050203128A1 (en) * 2004-03-13 2005-09-15 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
WO2006019831A1 (fr) * 2004-07-14 2006-02-23 Ptc Therapeutics, Inc. Procedes pour le traitement de l'hepatite c
WO2006036816A2 (fr) * 2004-09-24 2006-04-06 Smithkline Beecham Corporation Composes chimiques
WO2006054143A1 (fr) * 2004-11-17 2006-05-26 Pfizer Inc. Formes polymorphes de {5-[3-(4,6-difluoro-1h-benzimidazol-2-yl)-1h-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-ethyl-amine
WO2006091858A1 (fr) * 2005-02-25 2006-08-31 Rigel Pharmaceuticals, Inc. Benzisothiazoles utiles dans le traitement ou la prevention de l'infection a vhc
WO2006109633A1 (fr) * 2005-04-07 2006-10-19 Daiichi Sankyo Company, Limited Composé indole substitué
WO2007023381A1 (fr) * 2005-08-24 2007-03-01 Pfizer Inc. Methodes servant a preparer des inhibiteurs de hcv polymerase
WO2007076286A2 (fr) * 2005-12-16 2007-07-05 Smithkline Beecham Corporation Composes chimiques
WO2007076228A2 (fr) * 2005-12-20 2007-07-05 Boehringer Ingelheim International Gmbh Inhibiteurs de kinases tec
WO2007071434A1 (fr) * 2005-12-22 2007-06-28 Smithkline Beecham Corporation Composes antiviraux contenant du 2-carboxy-thiophene
WO2007117401A2 (fr) * 2006-04-07 2007-10-18 Janssen Pharmaceutica N.V. Indoles et benzoimidazoles modulateurs du récepteur de l'histamine h4
WO2008055808A1 (fr) * 2006-11-09 2008-05-15 F. Hoffmann-La Roche Ag Dérivés d'indole et de benzofuran 2-carboxamide

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 10181898 2005, XP002504031 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 11322868 2007, XP002504032 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 1244371 1975, XP002504021 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 1572685 2001, XP002504019 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 182734 2003, XP002504022 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 182734 2003, XP002504029 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 4469 1872, XP002504018 & HOBRECKER: CHEMISCHE BERICHTE, VERLAG CHEMIE GMBH. WEINHEIM, DE, vol. 5, 1872, page 920, ISSN: 0009-2940 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 4488201 1984, XP002504023 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 4544290 1989, XP002504026 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 4990072 1989, XP002504020 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 4997975 2005, XP002504028 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 9499037 2005, XP002504025 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 9515645 2003, XP002504027 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 9515667 2003, XP002504024 *
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; BRN 9641112 2003, XP002504030 *
HARPER S ET AL: "POTENT INHIBITORS OF SUBGENOMIC HEPATITIS C VIRUS RNA REPLICATION THROUGH OPTIMIZATION OF INDOLE-N-ACETAMIDE ALLOSTERIC INHIBITORS OF THE VIRAL NS5B POLYMERASE" JOURNAL OF MEDICINAL AND PHARMACEUTICAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 48, no. 14, 14 July 2005 (2005-07-14), pages 4547-4557, XP009071449 *
ZOU R ET AL: "Design, synthesis, and antiviral evaluation of 2-substituted 4,5-dichloro- and 4,6-dichloro-1-beta-D-ribofuranosylbenzimi dazoles as potential agents for human cytomegalovirus infections." JOURNAL OF MEDICINAL CHEMISTRY 28 FEB 1997, vol. 40, no. 5, 28 February 1997 (1997-02-28), pages 802-810, XP002504017 ISSN: 0022-2623 *

Cited By (216)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009112651A1 (fr) * 2008-01-02 2009-09-17 Sanofi-Aventis Dérivés d'mtoazo[1,2-a]pyridine-2-carboxamides, leur préparation et leur application en thérapeutique
US9018217B2 (en) 2008-06-20 2015-04-28 H. Lundbeck A/S Phenylimidazole derivatives as PDE10A enzyme inhibitors
US8865711B2 (en) 2008-06-20 2014-10-21 H. Lundbeck A/S Phenylimidazole derivatives as PDE10A enzyme inhibitors
US8841297B2 (en) 2008-06-20 2014-09-23 H. Lundbeck A/S Phenylimidazole derivative as PDE10A enzyme inhibitor
US8133897B2 (en) 2008-06-20 2012-03-13 H. Lundbeck A/S Phenylimidazole derivatives as PDE10A enzyme inhibitors
US9592230B2 (en) 2008-06-20 2017-03-14 H. Lundbeck A/S Substituted imidazoles as PDE10A inhibitors
US10117873B2 (en) 2008-08-11 2018-11-06 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US9877968B2 (en) 2008-08-11 2018-01-30 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US8501767B2 (en) 2008-09-16 2013-08-06 Csir Imidazopyridines and imidazopyrimidines as HIV-1 reverse transcriptase inhibitors
WO2010032195A1 (fr) * 2008-09-16 2010-03-25 Csir Imidazopyridines et imidazopyrimidines utilisés comme inhibiteurs de la transcriptase inverse du vih-1
US8524717B2 (en) 2008-10-17 2013-09-03 Oryzon Genomics, S.A. Oxidase inhibitors and their use
US8242125B2 (en) 2008-12-09 2012-08-14 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8431584B2 (en) 2008-12-09 2013-04-30 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8541432B2 (en) 2008-12-09 2013-09-24 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8486954B2 (en) 2008-12-09 2013-07-16 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8492393B2 (en) 2008-12-09 2013-07-23 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8501756B2 (en) 2008-12-09 2013-08-06 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8993808B2 (en) 2009-01-21 2015-03-31 Oryzon Genomics, S.A. Phenylcyclopropylamine derivatives and their medical use
US11053243B2 (en) 2009-03-27 2021-07-06 Merck Sharp & Dohme Corp. Inhibitors of hepatitis C virus replication
US9090661B2 (en) 2009-03-27 2015-07-28 Merck Sharp & Dohme Corp. Inhibitors of hepatitis C virus replication
US8778972B2 (en) 2009-05-15 2014-07-15 Novartis Ag 5-pyridin-3-yl-1, 3-dihydro-indol-2-on derivatives and their use as modulators of aldosterone synthase and/or CYP11B1
US8455522B2 (en) 2009-05-15 2013-06-04 Novartis Ag Benzoxazolone derivatives as aldosterone synthase inhibitors
US8633173B2 (en) 2009-06-05 2014-01-21 Cephalon, Inc Preparation and uses of 1,2,4-triazolo [1,5a] pyridine derivatives
US8501936B2 (en) 2009-06-05 2013-08-06 Cephalon, Inc. Preparation and uses of 1,2,4-triazolo [1,5a] pyridine derivatives
JP2017141271A (ja) * 2009-08-17 2017-08-17 インテリカイン， エルエルシー 複素環式化合物およびそれらの使用
US11547697B2 (en) 2009-08-17 2023-01-10 Millennium Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8859555B2 (en) 2009-09-25 2014-10-14 Oryzon Genomics S.A. Lysine Specific Demethylase-1 inhibitors and their use
WO2011041713A3 (fr) * 2009-10-02 2012-04-05 Glaxosmithkline Llc Agents anti-viraux à base de pipérazinyle
WO2011041713A2 (fr) * 2009-10-02 2011-04-07 Glaxosmithkline Llc Agents anti-viraux à base de pipérazinyle
US8946296B2 (en) 2009-10-09 2015-02-03 Oryzon Genomics S.A. Substituted heteroaryl- and aryl-cyclopropylamine acetamides and their use
US9051296B2 (en) 2009-11-16 2015-06-09 Raqualia Pharma Inc. Aryl carboxamide derivatives as TTX-S blockers
WO2011058766A1 (fr) * 2009-11-16 2011-05-19 Raqualia Pharma Inc. Dérivés d'arylcarboxamide comme bloqueurs de ttx-s
WO2011097491A1 (fr) * 2010-02-04 2011-08-11 Glaxosmithkline Llc Agents antiviraux à base de benzimidazole
US9186337B2 (en) 2010-02-24 2015-11-17 Oryzon Genomics S.A. Lysine demethylase inhibitors for diseases and disorders associated with Hepadnaviridae
US9616058B2 (en) 2010-02-24 2017-04-11 Oryzon Genomics, S.A. Potent selective LSD1 inhibitors and dual LSD1/MAO-B inhibitors for antiviral use
JP2013522191A (ja) * 2010-03-10 2013-06-13 ブリストル−マイヤーズ スクイブ カンパニー Ｃ型肝炎の処置のための化合物
US10202330B2 (en) 2010-04-19 2019-02-12 Oryzon Genomics, Sa Lysine specific demethylase-1 inhibitors and their use
US9149447B2 (en) 2010-04-19 2015-10-06 Oryzon Genomics S.A. Lysine specific demethylase-1 inhibitors and their use
WO2012008508A1 (fr) * 2010-07-14 2012-01-19 武田薬品工業株式会社 Composé hétérocyclique
US9708309B2 (en) 2010-07-29 2017-07-18 Oryzon Genomics, S.A. Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use
US9006449B2 (en) 2010-07-29 2015-04-14 Oryzon Genomics, S.A. Cyclopropylamine derivatives useful as LSD1 inhibitors
US10233178B2 (en) 2010-07-29 2019-03-19 Oryzon Genomics, S.A. Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use
US9676701B2 (en) 2010-07-29 2017-06-13 Oryzon Genomics, S.A. Cyclopropylamine derivatives useful as LSD1 inhibitors
US9181198B2 (en) 2010-07-29 2015-11-10 Oryzon Genomics S.A. Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use
US9254292B2 (en) 2010-09-29 2016-02-09 Merck Sharp & Dohme Corp. Fused tetracycle derivatives and methods of use thereof for the treatment of viral diseases
US9061966B2 (en) 2010-10-08 2015-06-23 Oryzon Genomics S.A. Cyclopropylamine inhibitors of oxidases
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US9790196B2 (en) 2010-11-30 2017-10-17 Oryzon Genomics S.A. Lysine demethylase inhibitors for diseases and disorders associated with Flaviviridae
WO2012072713A3 (fr) * 2010-11-30 2013-04-04 Oryzon Genomics, S.A. Inhibiteurs de la déméthylase spécifique de la lysine pour des maladies et troubles liés aux flaviviridés
US9908859B2 (en) 2011-02-08 2018-03-06 Oryzon Genomics, S.A. Lysine demethylase inhibitors for myeloproliferative disorders
US9107411B2 (en) 2011-03-09 2015-08-18 Bayer Intellectual Property Gmbh Indolecarboxamides and benzimidazolecarboxamides as insecticides and acaricides
WO2012119984A1 (fr) 2011-03-09 2012-09-13 Bayer Cropscience Ag Amides d'acide carboxylique d'indole et de benzimidazole utilisés comme insecticides et acaricides
US9504690B2 (en) 2011-03-17 2016-11-29 Merck Sharp & Dohme Corp. Tetracyclic xanthene derivatives and methods of use thereof for the treatment of viral diseases
US8748435B2 (en) 2011-04-01 2014-06-10 Novartis Ag Pyrazolo pyrimidine derivatives
US10420767B2 (en) 2011-04-08 2019-09-24 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US10272085B2 (en) 2011-04-08 2019-04-30 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US10780089B2 (en) 2011-04-08 2020-09-22 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US11541050B2 (en) 2011-04-08 2023-01-03 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US9422250B2 (en) 2011-04-08 2016-08-23 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
WO2012143796A3 (fr) * 2011-04-21 2013-06-27 Institut Pasteur Korea Composés anti-inflammatoires
WO2012143796A2 (fr) * 2011-04-21 2012-10-26 Institut Pasteur Korea Composés anti-inflammatoires
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US9096527B2 (en) 2011-06-24 2015-08-04 Amgen Inc. TRPM8 antagonists and their use in treatments
US10112946B2 (en) 2011-07-22 2018-10-30 Glaxosmithkline Llc Composition
WO2013025992A1 (fr) 2011-08-17 2013-02-21 Glaxosmithkline Llc Procédés thérapeutiques
US9487512B2 (en) 2011-10-20 2016-11-08 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US10329256B2 (en) 2011-10-20 2019-06-25 Oryzon Genomics, S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US10214477B2 (en) 2011-10-20 2019-02-26 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US9469597B2 (en) 2011-10-20 2016-10-18 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US9670136B2 (en) 2011-10-20 2017-06-06 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US9944601B2 (en) 2011-10-20 2018-04-17 Oryzon Genomics, S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US10280167B2 (en) 2011-11-09 2019-05-07 Janssen Sciences Ireland Uc Purine derivatives for the treatment of viral infections
US11104678B2 (en) 2011-11-09 2021-08-31 Janssen Sciences Ireland Unlimited Company Purine derivatives for the treatment of viral infections
US10047103B2 (en) 2012-04-26 2018-08-14 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
US9862730B2 (en) 2012-04-26 2018-01-09 Bristol-Myers Squibb Company Imidazothiadiazole derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
US10428077B2 (en) 2012-04-26 2019-10-01 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor4 (PAR4) inhibitors for treating platelet aggregation
US9518064B2 (en) 2012-04-26 2016-12-13 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyridazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
US9688695B2 (en) 2012-04-26 2017-06-27 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation
US10822343B2 (en) 2012-04-26 2020-11-03 Bristol-Myers Squibb Company Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor4 (PAR4) inhibitors for treating platelet aggregation
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US10822349B2 (en) 2012-07-13 2020-11-03 Janssen Sciences Ireland Unlimited Company Macrocyclic purines for the treatment of viral infections
US10280180B2 (en) 2012-07-13 2019-05-07 Janssen Sciences Ireland Uc Macrocyclic purines for the treatment of viral infections
US9381191B2 (en) 2012-07-20 2016-07-05 Metabrain Research Imidazopyridine derivatives useful in treating diabetes
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
WO2014026984A1 (fr) 2012-08-17 2014-02-20 Bayer Cropscience Ag Amides d'acide azaindole-carboxylique et thiocarboxylique comme insecticides et acaricides
US9555036B2 (en) 2012-08-24 2017-01-31 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US10022442B2 (en) 2012-08-24 2018-07-17 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US9662336B2 (en) 2012-08-24 2017-05-30 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US10259814B2 (en) 2012-10-10 2019-04-16 Janssen Sciences Ireland Uc Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US11220504B2 (en) 2012-10-10 2022-01-11 Janssen Sciences Ireland Unlimited Company Pyrrolo[3,2-d] pyrimidine derivatives for the treatment of viral infections and other diseases
US10723707B2 (en) 2012-11-16 2020-07-28 Janssen Sciences Ireland Unlimited Company Heterocyclic substituted 2-amino quinazoline derivatives for the treatment of viral infections
US10253003B2 (en) 2012-11-16 2019-04-09 Janssen Sciences Ireland Uc Heterocyclic substituted 2-amino quinazoline derivatives for the treatment of viral infections
US9428512B2 (en) 2012-11-20 2016-08-30 Glaxosmithkline Llc Compounds
US9907847B2 (en) 2012-11-20 2018-03-06 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9540383B2 (en) 2012-11-20 2017-01-10 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9550785B2 (en) 2012-11-20 2017-01-24 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9555038B2 (en) 2013-01-16 2017-01-31 Merck Sharp & Dohme Corp. Heterocycle-substituted tetracyclic compounds and methods of use thereof for the treatment of viral diseases
US10647684B2 (en) 2013-02-21 2020-05-12 Janssen Sciences Ireland Unlimited Company 2-aminopyrimidine derivatives for the treatment of viral infections
US10259793B2 (en) 2013-02-21 2019-04-16 Janssen Sciences Ireland Uc 2-aminopyrimidine derivatives for the treatment of viral infections
WO2014133008A1 (fr) 2013-02-27 2014-09-04 塩野義製薬株式会社 Dérivés d'indole et d'azaindole ayant chacun une activité d'activation d'ampk
US9890119B2 (en) 2013-02-27 2018-02-13 Shionogi & Co., Ltd. Indole and azaindole derivative having AMPK-activating activity
US10787453B2 (en) 2013-03-14 2020-09-29 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US11919913B2 (en) 2013-03-14 2024-03-05 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US11028098B2 (en) 2013-03-14 2021-06-08 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10421720B2 (en) 2013-03-14 2019-09-24 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9926271B2 (en) 2013-03-14 2018-03-27 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10570148B2 (en) 2013-03-14 2020-02-25 The Trustees Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US10266543B2 (en) 2013-03-29 2019-04-23 Janssen Sciences Ireland Uc Macrocyclic deaza-purinones for the treatment of viral infections
US11702426B2 (en) 2013-03-29 2023-07-18 Janssen Sciences Ireland Unlimited Company Macrocyclic deaza-purinones for the treatment of viral infections
US10829494B2 (en) 2013-03-29 2020-11-10 Janssen Sciences Ireland Unlimited Company Macrocyclic deaza-purinones for the treatment of viral infections
US10377738B2 (en) 2013-05-24 2019-08-13 Janssen Sciences Ireland Unlimited Company Pyridone derivatives for the treatment of viral infections and further diseases
US10865193B2 (en) 2013-05-24 2020-12-15 Janssen Sciences Ireland Unlimited Company Pyridone derivatives for the treatment of viral infections and further diseases
US10781216B2 (en) 2013-06-27 2020-09-22 Janssen Sciences Ireland Unlimited Company Pyrrolo [3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US10385054B2 (en) 2013-06-27 2019-08-20 Janssen Sciences Ireland Unlimited Company Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US10822347B2 (en) 2013-07-30 2020-11-03 Janssen Sciences Ireland Unlimited Company Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections
US10316043B2 (en) 2013-07-30 2019-06-11 Janssen Sciences Ireland Unlimited Company Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections
US9969687B2 (en) 2013-12-23 2018-05-15 Norgine B.V. Compounds useful as CCR9 modulators
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493450B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493442B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10174030B2 (en) 2014-02-13 2019-01-08 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10513493B2 (en) 2014-02-13 2019-12-24 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10676457B2 (en) 2014-02-13 2020-06-09 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10717737B2 (en) 2014-02-13 2020-07-21 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9994546B2 (en) 2014-02-13 2018-06-12 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10300051B2 (en) 2014-02-13 2019-05-28 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US11247992B2 (en) 2014-02-13 2022-02-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US11155532B2 (en) 2014-02-13 2021-10-26 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10072016B2 (en) 2014-04-30 2018-09-11 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10407433B2 (en) 2014-04-30 2019-09-10 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US11649240B2 (en) 2014-04-30 2023-05-16 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9777010B2 (en) 2014-04-30 2017-10-03 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10913746B2 (en) 2014-04-30 2021-02-09 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
WO2015169776A1 (fr) 2014-05-08 2015-11-12 Bayer Cropscience Ag Sulfonamides de pyrazolopyridine en tant que nématicides
US9617279B1 (en) 2014-06-24 2017-04-11 Bristol-Myers Squibb Company Imidazooxadiazole compounds
US9598419B1 (en) 2014-06-24 2017-03-21 Universite De Montreal Imidazotriazine and imidazodiazine compounds
US10138249B2 (en) 2014-07-10 2018-11-27 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US10968221B2 (en) 2014-07-10 2021-04-06 Incyte Corporation Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US10556908B2 (en) 2014-07-10 2020-02-11 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US10047086B2 (en) 2014-07-10 2018-08-14 Incyte Corporation Imidazopyridines and imidazopyrazines as LSD1 inhibitors
US10640503B2 (en) 2014-07-10 2020-05-05 Incyte Corporation Imidazopyridines and imidazopyrazines as LSD1 inhibitors
US10125133B2 (en) 2014-07-10 2018-11-13 Incyte Corporation Substituted [1,2,4]triazolo[1,5-a]pyridines and substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
US10112950B2 (en) 2014-07-10 2018-10-30 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US10100027B2 (en) 2014-09-26 2018-10-16 Changzhou Yinsheng Pharmaceutical Co., Ltd. Benzofuran analogue as NS4B inhibitor
US10118930B2 (en) 2014-11-03 2018-11-06 Bayer Pharma Aktiengesellschaft Piperidinylpyrazolopyrimidinones and their use
US9822130B2 (en) 2014-11-21 2017-11-21 Merck Sharp & Dohme Corp. Triazolo-pyrazinyl derivatives useful as soluble guanylate cyclase activators
US11401272B2 (en) 2015-04-03 2022-08-02 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US10800779B2 (en) 2015-04-03 2020-10-13 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US10188108B2 (en) 2015-04-08 2019-01-29 Bayer Cropscience Aktiengesellschaft Fused bicyclic heterocycle derivatives as pesticides
WO2016162318A1 (fr) * 2015-04-08 2016-10-13 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycles bicycliques condensés utilisés en tant que produits de lutte antiparasitaire, et leurs produits intermédiaires
US11084826B2 (en) 2015-04-28 2021-08-10 Janssen Sciences Ireland Unlimited Company RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US10611769B2 (en) 2015-04-28 2020-04-07 Janssen Sciences Ireland Unlimited Company RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US10208048B2 (en) 2015-04-28 2019-02-19 Janssen Sciences Ireland Uc RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US10723700B2 (en) 2015-08-12 2020-07-28 Incyte Corporation Salts of an LSD1 inhibitor
US11498900B2 (en) 2015-08-12 2022-11-15 Incyte Corporation Salts of an LSD1 inhibitor
US10329255B2 (en) 2015-08-12 2019-06-25 Incyte Corporation Salts of an LSD1 inhibitor
AU2016363937B2 (en) * 2015-11-30 2021-07-08 Oxford University Innovation Limited Inhibitors of metallo-beta-lactamases
US11439622B2 (en) 2015-11-30 2022-09-13 Oxford University Innovation Limited Inhibitors of metallo-beta-lactamases
WO2017093180A1 (fr) 2015-12-01 2017-06-08 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycles bicycliques condensés utilisés en tant que produits de lutte antiparasitaire
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
EP3241830A1 (fr) 2016-05-04 2017-11-08 Bayer CropScience Aktiengesellschaft Derivés de bicycles condensés hétérocycliques utilisés comme pesticides
US11780837B2 (en) 2016-06-21 2023-10-10 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US11332470B2 (en) 2016-06-21 2022-05-17 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US11306088B2 (en) 2016-06-21 2022-04-19 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US11053256B2 (en) 2016-07-01 2021-07-06 Janssen Sciences Ireland Unlimited Company Dihydropyranopyrimidines for the treatment of viral infections
WO2018033455A1 (fr) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
US10968184B2 (en) 2016-09-29 2021-04-06 Janssen Sciences Ireland Unlimited Company Pyrimidine prodrugs for the treatment of viral infections and further diseases
US10696666B2 (en) 2016-10-18 2020-06-30 CellCentric Limited Pharmaceutical compounds
US11377443B2 (en) 2016-10-18 2022-07-05 CellCentric Limited Pharmaceutical compounds
WO2018130443A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2018130437A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2019054427A1 (fr) 2017-09-14 2019-03-21 第一三共株式会社 Composé à structure cyclique
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
WO2019068572A1 (fr) 2017-10-04 2019-04-11 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11339165B2 (en) 2017-11-29 2022-05-24 Janssen Sciences Ireland Unlimited Company Pyrazolopyrimidines having activity against the respiratory syncytial virus (RSV)
US11491157B2 (en) 2018-01-31 2022-11-08 Janssen Sciences Ireland Unlimited Company Co Cork, IE Cycloalkyl substituted pyrazolopyrimidines having activity against RSV
WO2019162174A1 (fr) 2018-02-21 2019-08-29 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
US11673894B2 (en) 2018-02-27 2023-06-13 Incyte Corporation Imidazopyrimidines and triazolopyrimidines as A2A / A2B inhibitors
US11597704B2 (en) 2018-03-01 2023-03-07 Janssen Sciences Ireland Unlimited Company 2,4-diaminoquinazoline derivatives and medical uses thereof
WO2019175046A1 (fr) 2018-03-12 2019-09-19 Bayer Aktiengesellschaft Dérivés hétérocycliques bicycliques condensés utilisés comme pesticides
US11352356B2 (en) 2018-03-13 2022-06-07 Takeda Pharmaceutical Company Limited Inhibitors of plasma kallikrein and uses thereof
US10730874B2 (en) 2018-03-13 2020-08-04 Shire Human Genetic Therapies, Inc. Inhibitors of plasma kallikrein and uses thereof
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US11453662B2 (en) 2018-04-18 2022-09-27 Cellcentric Ltd Process for preparing modulators of p300 and/or CBP
WO2019201921A1 (fr) 2018-04-20 2019-10-24 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
US11708369B2 (en) 2018-04-23 2023-07-25 Janssen Sciences Ireland Unlimited Company Heteroaromatic compounds having activity against RSV
WO2019219517A1 (fr) 2018-05-17 2019-11-21 Bayer Aktiengesellschaft Dérivés de dihydropyrazolo pyrazine carboxamide substitués
US11873304B2 (en) 2018-05-18 2024-01-16 Incyte Corporation Fused pyrimidine derivatives as A2A/A2B inhibitors
US11168089B2 (en) 2018-05-18 2021-11-09 Incyte Corporation Fused pyrimidine derivatives as A2A / A2B inhibitors
US11161850B2 (en) 2018-07-05 2021-11-02 Incyte Corporation Fused pyrazine derivatives as A2A / A2B inhibitors
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US11512064B2 (en) 2018-08-31 2022-11-29 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11944622B2 (en) 2018-10-05 2024-04-02 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11884665B2 (en) 2019-01-29 2024-01-30 Incyte Corporation Pyrazolopyridines and triazolopyridines as A2A / A2B inhibitors
US11390624B2 (en) 2019-01-29 2022-07-19 Incyte Corporation Pyrazolopyridines and triazolopyridines as A2A / A2B inhibitors
US11370803B2 (en) 2019-09-18 2022-06-28 Takeda Pharmaceutical Company Limited Heteroaryl plasma kallikrein inhibitors
US11787796B2 (en) 2019-09-18 2023-10-17 Takeda Pharmaceutical Company Limited Plasma Kallikrein inhibitors and uses thereof
US11484597B2 (en) 2019-09-19 2022-11-01 Totus Medicines Inc. Therapeutic conjugates
WO2022087422A1 (fr) * 2020-10-22 2022-04-28 Chulalongkorn University Dérivés pyrrolidine-3-carboxamide et utilisations de ces derniers
WO2023057394A1 (fr) 2021-10-04 2023-04-13 Forx Therapeutics Ag Dérivés de n,n-diméthyl-4-(7-(n-(1-méthylcyclopropyl)sulfamoyl)-imidazo[1,5-a]pyridin-5-yl)pipérazine-1-carboxamide et dérivés correspondants de pyrazolo[1,5-a]pyridine utilisés en tant qu'inhibiteurs de parg pour le traitement du cancer

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